Novel fused thiazolo and oxazolo pyrimidinones

ABSTRACT

The present invention relates to novel compounds, their pharmaceutically acceptable salts, and their isomers, stereoisomers, conformers, tautomers, polymorphs, hydrates and solvates. The present invention also encompasses pharmaceutically acceptable compositions of said compounds and process for preparing novel compounds. The invention further relates to the use of the above-mentioned compounds for the preparation of medicament for use as pharmaceuticals.

CROSS REFERENCE TO RELATED APPLICATION(S)

This application claims priority to U.S. Application Ser. No. 61/264,734filed on Oct. 27, 2009, which application is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to novel thiazolo and oxazolo pyrimidinonecompounds of formula (I), their pharmaceutically acceptable salts, andtheir isomers, stereoisomers, conformers, tautomers, polymorphs,hydrates and solvates. The present invention also encompassespharmaceutically acceptable compositions of said compounds and processfor preparing novel compounds. The invention further relates to the useof the above-mentioned compounds for the preparation of medicament foruse as pharmaceuticals.

BACKGROUND OF THE INVENTION

The transcription factor HIF (Hypoxia Inducible Factor) has a centralrole in oxygen homeostasis. An early response to tissue hypoxia isinduction of Hypoxia Inducible Factor (HIF), a basic helix-loop-helix(bHLH) PAS (Per/Arnt/Sim) transcriptional activator that mediateschanges in gene expression in response to changes in cellular oxygenconcentration. HIF is a heterodimer consisting of a constitutivelyexpressed beta subunit and one of the two alpha subunits, HIFα1 andHIFα2.¹

In oxygenated (normoxic) cells, HIFα subunits are rapidly degraded by amechanism that involves ubiquitination by the von Hippel-Lindau tumorsuppressor (pVHL) E3 ligase complex. Under hypoxic conditions, HIFα isnot degraded, and an active HIFα/β complex accumulates in the nucleusand activates the expression of several genes including glycolyticenzymes, glucose transporter (GLUT)-1, erythropoietin (EPO), vascularendothelial growth factor (VEGF) and adrenomedullin.¹

Thus, HIF activation is one of the prominent adaptive mechanismsassociated with hypoxia/ischemia. As mentioned, HIF activation resultsin enhanced expression of genes which perform multiple functions to copeup with and to recover from hypoxic/ischemic conditions.²

In oxygenated cells (normoxic), two conserved proline residues of HIFαsubunits undergo hydroxylation. This reaction is catalysed by HIFprolyl-hydroxylases (PHD). Prolyl hydroxylated HIFα interacts with pVHLand rapidly gets degraded by proteasome machinery. In addition, innormoxic cells, one conserved asparagine of HIFα also undergoeshydroxylation. This reaction is catalysed by HIF asparagyl hydroxylase(FIH). Asparagyl hydroxylated HIFα can not interact with transcriptionalco-activator CBP/p300.

Under hypoxic/ischemic conditions, both HIF prolyl and HIF aspargylhydroxylase activities are drastically lowered due to limiting amount ofmolecular oxygen. As a result, HIFα is not destined for proteasomedegradation and hence stabilized. Further, HIFα can interact withtranscriptional co-activator CBP/p300. Such stabilized andtranscriptionally active HIFα then forms heterodimer with HIF-betasubunit and translocates to the nucleus and bring about transactivationof HIF target genes¹.

Inhibition of HIF prolyl hydroxylases and HIF asparagyl hydroxylase,thus can be a powerful approach for oxygen—independent activation ofHIF. Such HIF activation by pharmacological means results in enhancedexpression of genes which perform multiple functions to cope up with andto recover from hypoxic/ischemic conditions. HIF targets include genesresponsible for vasomotor regulation (e.g. Adrenomedullin, eNOS, HaemOxygrenase), energy metabolism (e.g. Glut-1, carbonic anhydrase-9),angiogenic signaling (e.g. VEGF, VEGF receptor-1) and erythropoiesis(e.g. Erythropoietin, Transferrin, transferrin receptor)¹. Therefore,HIF activation can offer significant therapeutic benefits in variousdisease conditions such as anemia of various types and tissue injuriescaused by hypoxia/ischemia in conditions like acute kidney injury,myocardial infarction, stroke, hepatic ischemia-reperfusion injury,peripheral vascular diseases and transplantation of liver orkidney^(3,4,5,6,7,8)

Anemia is characterised by decrease in normal number of red blood cells,which is generally caused by loss of blood (hemorrhage), excessive redblood cell destruction (hemolysis) or deficient red blood cellproduction (ineffective hematopoiesis). Since hemoglobin normallycarries oxygen from the lungs to the tissues, anemia leads to hypoxia inorgans. Since all human cells depend on oxygen for survival, anemia canhave a wide range of clinical consequences.

Anemia occurs often in elderly, in cancer patients, particularly thosereceiving chemotherapy & undergoing radiation, patients with renaldiseases and in a wide variety of conditions associated with chronicdiseases. Frequently, the cause of anemia is reduced erythropoietin(EPO) production resulting in prevention of erythropoiesis.

Erythropoietin (EPO), a naturally occurring hormone that is produced inresponse to HIFα, stimulates the production of erythrocytes. EPO isnormally secreted by the kidneys, and endogenous EPO is increased underconditions of reduced oxygen (hypoxia)⁹.

Exogeneous administration of EPO is one of the accepted modalities oftreatment of anemia particularly in chronic renal failure patients,cancer patients undergoing radiation and/or chemotherapy; however itsuse is limited by high cost and increased risk for thrombosis andhypertension¹⁰.

Ischemia is defined as an absolute or relative shortage of oxygen to atissue or organ and can result from disorders such as atherosclerosis,diabetes, thromboembolisms, hypotension, etc. The heart, brain andkidney are especially sensitive to ischemic stress caused by low bloodsupply.

Ischemia can be an acute (sudden onset and short duration) or chronic(slow onset with long duration or frequent recurrence). Acute ischemiais often associated with regional, irreversible tissue necrosis (aninfarct), whereas chronic ischemia is usually associated with transienthypoxic tissue injury. If the decrease in perfusion is prolonged orsevere, however, chronic ischemia can also be associated with aninfarct. Infarctions commonly occur in the spleen, kidney, lungs, brain,and heart, producing disorders such as intestinal infarction, pulmonaryinfarction, ischemic stroke, and myocardial infarction.

Ischemic and hypoxic disorders are a major cause of morbidity andmortality.

Currently, treatment of ischemic and hypoxic disorders is focused onrelief of symptoms and treatment of causative disorders but none ofthese therapies directly address the tissue damage produced by theischemia and hypoxia.

Exogenous administration of some of the HIF target genes such aserythropoietin, VEGF, adrenomedullin has shown significant functionalrecovery in ischemia and ischemia-reperfusion injury of heart, kidney,brain and liver.^(11,12,13,14)

Due to deficiencies in current treatments of anemia & diseases due tohypoxia and ischemia, there remains a need for compounds that areeffective in treating anemias of different types such as anemia inelderly or anemia associated with chronic diseases or renal failure orcancer or infection or dialysis or surgery or chemotherapy and inischemic/hypoxic disorders such as acute kidney injury, myocardialinfarction, stroke, hepatic ischemia-reperfusion injury and peripheralvascular diseases.

The compounds of this invention provide a means for inhibiting HIFhydroxylases and thereby activating the HIF, which results in enhancedexpression of the wide spectrum of target genes including erythropoietin(EPO), vascular endothelial growth factor (VEGF), adrenomedullin etc.and thus useful in treating various disorders including anemia ofdifferent types and conditions associated with ischemia/hypoxia.

EP 661269 discloses substituted heterocyclic carboxylic acid amides andtheir use as inhibitors of prolyl-4-hydroxylase and as inhibitors ofcollagen biosynthesis.

Additionally, various patent publications such as WO2003049686,WO2003053997, WO2004108121, WO2007146425, WO2007146438 disclose thecompounds that stabilize HIFα and their use for the prevention andtreatment of conditions associated with ischemia & hypoxia and EPOassociated conditions like anemia and neurological disorders.

JP 5039293 discloses a various fused and substituted thiazolopyrimidinederivative or it's salt, useful as an immunomodulating agent.

International publications WO2009039321 and WO2009039322 disclosebicyclic heteroaromatic N-substituted glycine derivatives, which areantagonists of HIF prolyl hydroxylases and are useful for treatingdiseases benefiting from the inhibition of these enzymes like anemia.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides novel compounds offormula (I),

their pharmaceutically acceptable salts and their isomers,stereoisomers, conformers, tautomers, polymorphs, hydrates, andsolvates;

Wherein,

when Y is NR₄, O, S or SO₂, m is 1 to 2 and when Y is C(R₅)(R₆), m is 1to 4;

n is 1 to 6;

P is —OH, —OR₇, —NH₂, —NHR₇, —NR₇R_(7′), —NHSO₂R₇, —NHCOR₇, —NHOH or—NHOR₇;

X is —OH, —OR₇, —SR₇, —SOR₇, —SO₂R₇, —NHR₇ or —NR₇R_(7′);

Z is S or O;

R is hydrogen, linear or branched (C₁-C₈)alkyl, —(C₁-C₈)alkylaryl or—(C₁-C₈)alkylheteroaryl;

R₁ and R₂ are independently selected from hydrogen, linear or branched—(C₁-C₈)alkyl, —(C₃-C₇) cycloalkyl, aryl, heteroaryl, —CH₂-aryl and—CH₂-heteroaryl, or

R₁ and R₂ may join together to form a 3-6 membered monocyclic or 9-12membered bicyclic ring;

R together with either R₁ or R₂ of adjacent carbon atom may form a 3-6membered monocyclic or 8-11 membered bicyclic heteroaryl or heterocyclylring;

R₃ and R_(3′) at each occurrence is independently selected fromhydrogen, linear or branched (C₁-C₈)alkyl, (C₁-C₅) alkoxy and halo;

R₃ and R_(3′) may also present in gem di-halo, gem di-alkyl orspirocycloalkyl arrangement;

R₄ is selected from the group consisting of hydrogen, linear or branched(C₁-C₈) alkyl, (C₃-C₇) cycloalkyl, aryl, heteroaryl, —(C₁-C₈)alkyl-aryl, —(C₁-C₈)alkyl-heteroaryl, —(C₁-C₂)alkyl-heterocyclyl,—C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —C(S)NR₈R₉ and —SO₂R₈, wherein aryl andheteroaryl radicals are optionally substituted with one or moresubstituent selected from the group consisting of —(C₁-C₈) alkyl,—(C₃-C₇) cycloalkyl, heterocyclyl, aryl, heteroaryl, —OH, -alkoxy, halo,CN, —CF₃, —OCF₃, —O-aryl, —SO₂—(C₁-C₈)-alkyl, —SO₂-aryl, —NH₂, —NHR₁₀,—NR₁₀R_(10′), —NH—CO—(C₁-C₈) alkyl, —NH—SO₂—(C₁-C₈)alkyl, —NH—SO₂-aryl,—COOH, —C(O)NH-alkyl, —CONH-aryl, —CONH-heteroaryl, —C(O)O—(C₁-C₈)alkyl,—C(O)O-aryl, —SO₂NH—(C₁-C₈)alkyl, —SO₂NH-aryl and —SO₂NH-heteroaryl;

R₅ and R₆ are independently selected from the group consisting ofhydrogen, linear or branched (C₁-C₈)alkyl, (C₃-C₇) cycloalkyl, aryl,heteroaryl, fluoro, —COOH, —CONH—(C₁-C₈)alkyl, —NHCO—(C₁-C₈)alkyl,—NHCO-aryl, —NHCO-heteroaryl, —NH—SO₂(C₁-C₈)alkyl, —NH—SO₂-aryl and—NH—SO₂-heteroaryl;

R₅ and R₆ may join together to form a 3-6 membered carbocyclic,heteroaryl or heterocyclyl ring;

R₇, R_(7′), R₁₀ and R_(10′) are independently selected from linear orbranched (C₁-C₈)alkyl, (C₃-C₇) cycloalkyl and —(C₁-C₈)alkylaryl;

R₇ and R_(7′) or R₁₀ and R_(10′) together with nitrogen atom to whichthey are attached, may form 5-6 membered monocyclic or 8-14 memberedbicyclic saturated and partially saturated ring. The ring may contain 1to 3 heteroatom selected from N, S & O. Wherein saturated and partiallysaturated ring may be optionally substituted with one or moresubstituent independently selected from the group consisting of—(C₁-C₈)alkyl, —(C₃-C₇) cycloalkyl, heterocyclyl, aryl, heteroaryl, —OH,-alkoxy, halo, —CN, —CF₃, —OCF₃, —O-aryl, —SO₂—(C₁-C₈)-alkyl, —SO₂-aryl,—NH₂, —NHR₁₀, —NR₁₀R_(10′), —NH—CO—(C₁-C₈)alkyl, —NH—SO₂—(C₁-C₈)alkyl,—NH—SO₂-aryl, —COOH, —C(O)NH-alkyl, —CONH-aryl, —CONH-heteroaryl,—C(O)O—(C₁-C₈)alkyl, —C(O)O-aryl, —SO₂NH—(C₁-C₈)alkyl, —SO₂NH-aryl and—SO₂NH-heteroaryl;

R₈ is selected from the group consisting of linear or branched (C₁-C₈)alkyl, (C₃-C₇) cycloalkyl, —(C₁-C₈)alkyl-(C₃-C₇)cycloalkyl,heterocyclyl, aryl, —(C₁-C₈)alkyl-aryl, —(C₁-C₂)alkyl-heterocyclyl,heteroaryl and —(C₁-C₈)alkyl-heteroaryl, wherein aryl and heteroarylradicals are optionally substituted with one or more substituentselected from linear or branched (C₁-C₈)alkyl, (C₃-C₇)cycloalkyl,—(C₁-C₈)alkyl-(C₃-C₇)cycloalkyl, aryl, heteroaryl, heterocyclyl, —OH,alkoxy, halo, —CN, —CF₃, —OCF₃, —O-aryl, —SO₂—(C₁-C₈)alkyl, —SO₂-aryl,—NH₂, —NHR₁₀, —NR₁₀R_(10′), —NH—CO—(C₁-C₈)alkyl, —NH—SO₂—(C₁-C₈)alkyl,—C(O)OH, —C(O)NH—(C₁-C₈)alkyl, —CONH-aryl, —CONH-heteroaryl,—NHCONH—(C₁-C₈)alkyl, —NHCONH-aryl, —SO₂NH—(C₁-C₈)alkyl, —SO₂NH-aryl and—SO₂NH-heteroaryl;

R₉ is hydrogen, linear or branched (C₁-C₈)alkyl or —(C₁-C₈)alkylaryl;

R₈ and R₉ together with nitrogen atom to which they are attached, mayform 5-6 membered saturated ring.

In another embodiment, the present invention pertains to a compound asabove, however only including pharmaceutically acceptable salts thereof.

In another embodiment, the present invention includes syntheticintermediates that are useful in preparing the compounds of formula (I)and process for preparing such intermediates.

Another embodiment of the present invention is a method for preparationof a compound of formula (I) as herein described in Schemes A, B, C, D &E.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising a compound of formula (I), optionally inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier.

Another embodiment of the present invention is a method for treatinganemia by administering a therapeutically effective amount of a compoundof formula (I) to a mammal in need thereof.

Another embodiment of the present invention is a method for treatinganemia of elderly or anemia associated with conditions like chronicdiseases, renal failure, cancer, infection, dialysis, surgery, andchemotherapy by administering a therapeutically effective amount of acompound of formula (I) to a mammal in need thereof.

Another embodiment of the present invention is a method for preventionor treatment of tissue damage caused by renal ischemia, cardiovascularischemia, cerebrovascular ischemia, hepatic ischemia or peripheralvascular ischemia by administering a therapeutically effective amount ofa compound of formula (I) to a mammal in need thereof.

Another embodiment of the present invention is a method for preventionor treatment of tissue damage caused by ischemic disorders includingacute kidney injury, myocardial infarction, stroke, hepaticischemia-reperfusion injury and peripheral vascular diseases byadministering a therapeutically effective amount of a compound offormula (I) to a mammal in need thereof.

Another embodiment of the present invention is a method for preventionor treatment of tissue damage caused by ischemia-reperfusion injurywhile transplantation procedures of organs like liver or kidney byadministering a therapeutically effective amount of a compound offormula (I) to a mammal in need thereof.

Another embodiment of the present invention is the use of a compound offormula (I) for the preparation of a medicament for treating anemia.

Another embodiment of the present invention is the use of a compound offormula (I) for the preparation of a medicament for treating anemia ofelderly or anemia associated with conditions like chronic diseases,renal failure, cancer, infection, dialysis, surgery and chemotherapy.

Another embodiment of the present invention is the use of a compound offormula (I) for the preparation of a medicament for prevention ortreatment of tissue damage caused by renal ischemia, cardiovascularischemia, cerebrovascular ischemia, hepatic ischemia or peripheralvascular ischemia.

Another embodiment of the present invention is the use of a compound offormula (I) for the preparation of a medicament for prevention ortreatment of tissue damage caused by ischemic disorders including acutekidney injury, myocardial infarction, stroke, hepaticischemia-reperfusion injury and peripheral vascular diseases.

Another embodiment of the present invention is the use of a compound offormula (I) for the preparation of a medicament for prevention ortreatment of tissue damage caused by ischemia-reperfusion injury whiletransplantation procedures of organs like liver or kidney.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides novel compounds offormula (I),

their pharmaceutically acceptable salts and their isomers,stereoisomers, conformers, tautomers, polymorphs, hydrates and solvates,wherein R, R₁, R₂, R₃, R_(3′), X, Y, Z, m, n and P are as defined above.

A family of specific compounds of particular interest within the aboveformula (I) consists of compound and pharmaceutically acceptable saltsthereof as follows:

Compd. No. Chemical Name 1[(2-Hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid 23-(Carboxymethyl-carbamoyl)-2-hydroxy-4-oxo-5,8-dihydro-4H,6H-9-thia-1,4a,7-triaza-fluorene-7-carboxylic acid ethyl ester 3[(2-Hydroxy-7-methanesulfonyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-acetic acid 4{[2-Hydroxy-7-(3-methyl-butyryl)-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 5{[2-Hydroxy-4-oxo-7-(propane-2-sulfonyl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 61-[(2-Hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-cyclopentanecarboxylic acid 7{[2-Hydroxy-4-oxo-7-(toluene-4-sulfonyl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 8[(2-Hydroxy-4-oxo-7-phenylcarbamoyl-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-acetic acid 9[(7-Cyclopropanecarbonyl-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-acetic acid 10[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid 11[(2-Hydroxy-4-oxo-7,8-dihydro-4H,6H-cyclopenta[4,5]thiazolo[3,2-a]pyrimidine-3-carbonyl)-amino]-acetic acid 12[(2-Hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid, sodium salt 13[(7-tert-Butyl-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid 143-[(2-Hydroxy-4-oxo-7,8-dihydro-4H,6H-cyclopenta[4,5]thiazolo[3,2-a]pyrimidine-3-carbonyl)-amino]-propionic acid 153-[(7-tert-Butyl-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-propionic acid 16{[7-(4-Fluoro-benzoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 17{[7-(5-Chloro-thiophene-2-sulfonyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 18{[2-Hydroxy-4-oxo-7-(5-trifluoromethyl-pyridin-2-yl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 19{[2-Hydroxy-4-oxo-7-(4-trifluoromethoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid 20{[7-(2,2-Dimethyl-propionyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 21{[7-(4-Butyl-benzoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 22{[2-Hydroxy-4-oxo-7-(4-trifluoromethoxy-benzoyl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 23{[7-(4-Chloro-benzyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 24{[7-(4-Fluoro-phenylthiocarbamoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 25[(2-Hydroxy-7-isopropylthiocarbamoyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-acetic acid 263-(Carboxymethyl-carbamoyl)-2-hydroxy-4-oxo-5,8-dihydro-4H,6H-9-thia-1,4a,7-triaza-fluorene-7-carboxylic acid benzyl ester 27{[7-(2-Cyclopropyl-acetyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 28({7-[2-(4-Chloro-phenyl)-acetyl]-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl}-amino)-acetic acid 29{[7-(2-Cyclopentyl-acetyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 303-[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-propionic acid 31{[2-Hydroxy-7-(4-methoxy-benzyl)-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 322-[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-propionic acid 33{[7-(6-Chloro-pyridine-3-carbonyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 34[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid 35{[7-(6-Chloro-pyridazin-3-yl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 36{[7-(3-Cyano-pyridin-2-yl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 37{[7-(3-Chloro-4-methoxy-benzoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 38[(2-Hydroxy-4-oxo-5,6,7,8,9,10-hexahydro-4H-11-thia-1,4a-diaza-cycloocta[a]indene-3-carbonyl)-amino]-acetic acid 39[(2-Hydroxy-7-indan-5-ylmethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-acetic acid 402-[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-propionic acid 41{[7-(3,5-Dimethoxy-benzoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 42{[2-Hydroxy-7-(4-methanesulfonyl-benzoyl)-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 432-[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-3-methyl-butyric acid (L-isomer) 442-[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-propionic acid (D-isomer) 45{[7-(3,5-Dichloro-4-methoxy-benzoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 46{[7-(3,5-Bis-trifluoromethyl-benzyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 47{[2-Hydroxy-4-oxo-7-(4-propyl-benzoyl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 48{[7-(3,5-Bis-trifluoromethyl-benzoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 49{[7-(3,4-Dichloro-benzyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 50[(2-Hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-acetic acid, hydrochloride salt 51{[2-Hydroxy-7-(7-methoxy-6-methyl-indan-4-ylmethyl)-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid 52{[2-Hydroxy-4-oxo-7-(4-trifluoromethyl-benzyl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-acetic acid 53[(7,7-Diethyl-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid 542-[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-2-methyl-propionic acid 55[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-phenyl-acetic acid, L-isomer 56[(7-Benzoylamino-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid 57[(2-Hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-oxa-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid 58[(2-Hydroxy-7-methyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid 59[(2-Hydroxy-4-oxo-7-propyl-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid 60[(2-Hydroxy-6,6-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid 61[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-methyl-amino]-acetic acid 621-[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-cyclohexanecarboxylic acid 631-(7,7-Dimethyl-2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-piperidine-4-carboxylic acid 64[(2-Hydroxy-4-oxo-7-phenyl-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid 65[(2-Hydroxy-4-oxo-5,8-dihydro-4H,6H-7-oxa-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid 66[(2-Hydroxy-5,7,7-trimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid 67[(2-Hydroxy-4,7,7-trioxo-5,6,7,8-tetrahydro-4H-7lambda*6*,9-dithia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid 68[(2-Methylsulfanyl-4-oxo-5,8-dihydro-4H,6H-7,9-dithia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid 69[(5-Ethoxy-2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid ethyl ester 70N-[(2′-hydroxy-4′-oxo-6′,9′-dihydro-4′H,7′H-spiro[cyclopropane-1,8′-pyrimido[2,1-b][1,3]benzothiazol]-3′-yl)carbonyl]glycine 71[(7-Isopropyl-2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-acetic acid 723-(Carboxymethyl-carbamoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-7-carboxylic acid 73{[7-(3,5-Dimethyl-pyrazol-1-yl)-2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl]-amino}-acetic acid 742-[(2-Hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-3-methyl-pentanoic acid (L-isomer) 753-(1H-Indol-2-yl)-2-[(2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-propionic acid (L-isomer) 763-(3H-Imidazol-4-yl)-2-[(2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-propionic acid (L-isomer) 773-(4-Hydroxy-phenyl)-2-[(2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-propionic acid (L-isomer) 78[(2-Hydroxy-4-oxo-7-pyridin-4-ylmethyl-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-acetic acid 792-Methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylic acid (2-oxo-2-pyrrolidin-1-yl-ethyl)-amide80[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-acetic acid, Disodium salt 81[(2-Ethoxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid 82[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid, Disodium salt 83[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid, arginine salt (2:1) 84[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid, lysine salt 85[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid, dipotassium salt 86[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid, calcium salt (2:1) 87[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid, magnesium salt (2:1) 88[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid, ammonium salt 89[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid, diethylamine salt 90[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid, choline salt 91[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid, tromethamine salt 92[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid, histidine salt 832-Methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylic acid carbamoylmethyl-amide 842-Methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylic acid hydroxycarbamoylmethyl-amide 85[(4-Chloro-benzyl)-(2-methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid 864-[Cyclopentyl-(2-methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-butyric acid 972-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylic acid (2-oxo-2-pyrrolidin-1-yl-ethyl)-amide98 2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylic acid cyclohexylcarbamoylmethyl-amide 992-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylic acid (benzylcarbamoyl-methyl)-amide 1004-[Cyclopentyl-(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-butyric acid 101[Benzyl-(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid

DEFINITIONS

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances:

The term “compound” employed herein refers to any compound encompassedby the generic formula disclosed herein. The compounds described hereinmay contain one or more double bonds and therefore, may exist asisomers, stereoisomers, such as geometric isomers, E and Z isomers, andmay possess asymmetric carbon atoms (optical centres) and therefore mayexist as enantiomers, diastereoisomers. Accordingly, the chemicalstructures described herein encompasses all possible stereoisomers ofthe illustrated compounds including the stereoisomerically pure form(e.g., geometrically pure) and stereoisomeric mixtures (racemates). Thecompound described herein, may exist as a conformational isomers such aschair or boat form. The compounds may also exist in several tautomericforms including the enol form, the keto form and mixtures thereof.Accordingly, the chemical structures described herein encompass allpossible tautomeric forms of the illustrated compounds. The compoundsdescribed also include isotopically labeled compounds where one or moreatoms have an atomic mass different from the atomic mass conventionallyfound in nature. Examples of isotopes that may be incorporated into thecompounds of the invention include, but are not limited to ²H, ³H, ¹³ C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc. Compounds may exist in unsolvated forms as wellas solvated forms, including hydrated forms. In general, compounds maybe hydrated or solvated. Certain compounds may exist in multiplecrystalline or amorphous forms. In general, all physical forms areequivalent for the uses contemplated herein and are intended to bewithin the scope of the present invention.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext.

Further, it should be understood, when partial structures of thecompounds are illustrated, a dash (“-”) indicate the point of attachmentof the partial structure to the rest of the molecule.

The nomenclature of the compounds of the present invention as indicatedherein is according to ISIS® draw (version 2.2) from MDL & ACD/LabsPro-version 12.0.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include: (1) acid addition salts, formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid, and the like; or formed with organicacids such as acetic acid, propionic acid, isobutyric acid, hexanoicacid, cyclopentanepropionic acid, oxalic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, suberic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, 3-(4-hydroxybenzoyl)benzoic acid, phthalic acid, cinnamic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glucuronic acid, galactunoric acid,glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid,muconic acid, and the like; or (2) salts formed when an acidic protonpresent in the parent compound is replaced by a metal ion, e.g., analkali metal ion, an alkaline earth ion, or an aluminum ion; orcoordinates with an organic base such as ethanolamine, diethanolamine,triethanolamine, N-methylglucamine and the like. Also included are saltsof amino acids such as arginate and the like (see, for example, Berge,S. M., et al., “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19).

As used herein, the term “polymorph” pertains to compounds having thesame chemical formula, the same salt type and having the same form ofhydrate/solvate but having different crystallographic properties.

As used herein, the term “hydrate” pertains to a compound having anumber of water molecules bonded to the compound.

As used herein, the term “solvate” pertains to a compound having anumber of solvent molecules bonded to the compound.

The present invention also encompasses compounds which are in a prodrugform. Prodrugs of the compounds described herein are those compoundsthat readily undergo chemical changes under physiological conditions (invivo) to provide the compounds of the present invention. Additionally,prodrugs can be converted to the compounds of the present invention bychemical or biochemical methods in an ex vivo environment, for example,transdermal patch reservoir with a suitable enzyme or chemical. Prodrugsare, in some situation, easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent drug is not. The prodrug may also have improved solubility inpharmacological composition over the parent drug. Esters, peptidylderivatives and the like, of the compounds are the examples of prodrugsof the present invention. In vivo hydrolysable (or cleavable) ester of acompound of the present invention that contains a carboxy group is, forexample, a pharmaceutically acceptable ester which is hydrolysed in thehuman or animal body to produce the parent acid.

The term “substituted”, as used herein, includes mono- andpoly-substitution by a named substituent to the extent such single andmultiple substitution (including multiple substitution at the same site)is chemically allowed and which means that any one or more hydrogens onthe designated atom is replaced with a selection from the indicatedgroup, provided that the designated atom's normal valence is notexceeded, and that the substitution results in a stable compound, forexample, when a substituent is keto, then the two hydrogens on the atomare replaced. All substituents (R, R₁, R₂ . . . ) and their furthersubstituents described herein may be attached to the main structure atany heteroatom or carbon atom which results in formation of stablecompound.

As used herein, a “halo” or “halogen” substituent is a monovalenthalogen radical chosen from chloro, bromo, iodo and fluoro.

The term “alkyl” used either alone or in attachment with another grouprefers to a saturated aliphatic hydrocarbon radical having the indicatednumber of carbon atoms and that is unsubstituted or substituted. When asubscript is used with reference to an alkyl, the subscript refers tothe number of carbon atoms that group may contain. For example, a“C₁-C₆” would refer to any alkyl group containing one to six carbons inthe structure. Alkyl may be straight chain, branched chain or cyclic.The said alkyl may be optionally substituted with substituents atpositions that do not significantly interfere with the preparation ofcompounds falling within the scope of this invention. The said alkyl isoptionally substituted with one to two substituents independentlyselected from the group consisting of C₁₋₃alkoxy, amino,mono(C₁₋₃alkyl)amino, di(C₁₋₃alkyl)amino, C₁₋₃alkyl, and hydroxy.

The term “alkoxy” referees to any alkyl group as defined herein aboveattached to the parent molecular moiety through an oxygen bridge.

The term “aryl” refers to an aromatic group for example, which is a 6 to10 membered monocyclic or bicyclic carbon-containing ring system, whichmay be unsubstituted or substituted.

The term “heteroaryl” refers to an aromatic group for example, which isa 5 to 14 membered monocyclic or bicyclic ring system, which has atleast one heteroatom, which may be unsubstituted or substituted. Theterm “heteroatom” as used herein includes oxygen, sulfur and nitrogen.

The term “heterocyclyl” refers to a fully or partially saturated cyclicgroup, for example, which is a 3 to 14 membered monocyclic or bicyclicring system, which has at least one heteroatom, which may beunsubstituted or substituted. The term “heteroatom” as used hereinincludes oxygen, sulfur and nitrogen.

As used herein, “room temperature” refers to a temperature between 25°C. and 35° C.

As used herein, the term “mammal” means a human or an animal such asmonkeys, primates, dogs, cats, horses, cows, etc.

The terms “treating” or “treatment” of any disease or disorder as usedherein to mean administering a compound to a mammal in need thereof. Thecompound may be administered thereby providing a prophylactic effect interms of completely or partially preventing or delaying the onset of adisease or disorder or sign or symptom thereof; and/or the compound maybe administered thereby providing a partial or complete cure for adisease or disorder and/or adverse effect attributable to the disorder.

The phrase “a therapeutically effective amount” means the amount of acompound that, when administered to a patient for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,mode of administration, the disease and its severity and the age,weight, etc., of the patient to be treated.

Throughout this specification and the appended claims it is to beunderstood that the words “comprise” and “include” and variations suchas “comprises”, “comprising”, “includes”, “including” are to beinterpreted inclusively, unless the context requires otherwise. That is,the use of these words may imply the inclusion of an element or elementsnot specifically recited.

It has been surprisingly found that partially saturated tricycliccompounds containing one or more heteroatom exhibits better in-vitroactivity profile.

In another embodiment, present invention provides the process forpreparing the compounds of formula (I).

The following reaction schemes are given to disclose the synthesis ofthe compounds according to the present invention.

Accordingly, the compounds of formula (I) of the present invention maybe prepared as described in the schemes below.

Formula (I) includes, but is not limited to, compounds of formula (Ia),(Ib), (Ic), (Id), (Ie) (If), (Ig), (Ih), (Ii), (Ij) and (Ik); compoundof formula (Ia) includes, but is not limited to, compounds of formula(Ia-1) and (Ia-2); compound of formula (Ic) includes, but is not limitedto, compounds of formula (Ic-1), (Ic-2) and (Ic-3); compound of formula(Id) include, but is not limited to, compounds of formula (Id-1) and(Id-2).

The compound of formula (Ia-Ik), which belongs to general formula (I),can be prepared by the following methods described in schemes A, B, C, D& E.

Compounds belong to general formula (I) such as compound of formula(Ia), (Ib), (Ic) and (Id), can be synthesized from the compound offormula (III) and (IV) as shown in scheme A, wherein R, R₁, R₂, R₃,R_(3′), Z, m and n are as defined above while Y and R₄ are defined inscheme A.

In general, the compound of formula (Ia) can be prepared by reacting thecompound of formula (III) with various amino esters having the followinggeneral formula,

wherein, n, R, R₁, R₂ are as defined as above, using suitable couplingreagent such as carbodiimides, CDI (1,1′-Carbonyldiimidazole) or PyBop(benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) inthe presence of base like tertiary amine such as triethylamine and inaprotic solvent such as tetrahydrofuran, dichloromethane etc.

The compound of formula (Ib) can be prepared by the oxidation ofcompounds of formula (Ia) with suitable oxidizing reagent such asperacid or hydrogen peroxide in solvent like dioxan, tetrahydrofuran ordichloromethane at room temperature for 2-6 hrs. The compound of formula(Ib), upon alkaline hydrolysis in the presence of base including alkalihydroxide such as sodium hydroxide and in inert solvent liketetrahydrofuran, water or mixture thereof, provides compound of formula(Ic).

The compound of formula (III) can be prepared by heating appropriateamines of formula (II) with5-(bis-ethylsulfanyl-methylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione insuitable solvent such as alcoholic solvent or dimethylformamide at80-85° C. for 2-24 hrs.

The compound of formula (Id) can be prepared by reacting the compound offormula (IV) with various amino esters having the following generalformula,

wherein, n, R, R₁, R₂ are as defined as above, in suitable solvent andbase such as pyridine at 100-110° C. for 2 to 6 hrs.

The compound of formula (Ic) can also be prepared by alkaline hydrolysisof compound of formula (Id) in the presence of base including alkalihydroxide such as sodium hydroxide and in inert solvent liketetrahydrofuran, water or mixture thereof.

The compound of formula (IV) can be prepared by reacting the appropriateamines of formula (II) with triethyl methanetricarboxylate in suitablesolvent such as xylene, toluene or bromobenzene at elevated temperature.

The compound of formula (II) such as thiazole-2-amines (Z is S) oroxazole-2-amines (Z is O) is either synthesized using method describedin literature (US 2006/0252837, U.S. Pat. No. 4,423,048 and J. Med.Chemistry, 2002, 45(23), 5090-5097) or commercially available.

Several N-unsubstituted and N-substituted derivatives belongs to formula(I), such as compounds of formula (Ie), (Ia-2) and (Ic-1) can beprepared from the compound of formula (Ia-1), as shown in scheme B,wherein R, R₁, R₂, R₃, R_(3′), R₄, R₈, R₉, m and n are as defined above.

The compound of formula (Ic-1) can be prepared by oxidation of compoundsof formula (Ia-2) with peracid or hydrogen peroxide in solvent liketetrahydrofuran or dichloromethane at room temperature for 2-6 hrs,followed by basic hydrolysis in the presence of base including alkalihydroxide such as sodium hydroxide and in inert solvent liketetrahydrofuran, water or mixture thereof at room temperature for 2-6hrs.

The compound of formula (Ia-2) can be prepared by introducing various R₄groups in compound of formula (Ie), by reacting it with suitablereagents such as sulfonyl chlorides, carbonyl chlorides, chloroformates,isocyanates, carbamoyl chlorides, isothiocyanates and carbamothioicchloride in the presence of organic base such as triethylamine, pyridineor N-methylmorpholine and in solvent like tetrahydrofuran,dichloromethane or mixture thereof at room temperature for 2-8 hrs.

The compound of formula (Ie) can be prepared by the deprotection of Bocgroup in compounds of formula (Ia-1) using acidic reagent liketrifluoroacetic acid in inert solvent like tetrahydrofuran ordichloromethane at room temperature for 2-6 hrs.

The compound of formula (Ia-1) can be prepared from compound of formula(III) as described in Scheme-A.

In an alternate way, various N-unsubstituted and N-substitutedderivatives belongs to formula (I), such as compounds of formula (If),(Id-2) and (Ic-3) can be prepared from the compound of formula (Id-1) or(Ic-2), as shown in scheme C. wherein R, R₁, R₂, R₃, R_(3′), R₄, m and nare as defined above.

The compound of formula (Ic-3) can be prepared by alkaline hydrolysis ofcompounds of formula (Id-2) in the presence of base including alkalihydroxide such as sodium hydroxide and in inert solvent liketetrahydrofuran, water or mixture thereof at room temperature for 2-6hrs.

The compound of formula (Id-2) can be prepared by introducing various R₄group at nitrogen of compounds of formula (If) by reacting with R₄-Halo,wherein R₄ is —CH₂-aryl, in the presence of suitable base liketriethylamine, pyridine or N-methylmorpholine and solvent such asdichloromethane or tetrahydrofuran at room temperature for 5-12 hrs.

The compounds of formula (If) can be obtained by the esterification ofcompounds of formula (Ic-2) with ethanol in the presence of carbodiimidefollowed by removal of Boc group using acidic reagent liketrifluoroacetic acid in an inert solvent like tetrahydrofuran ordichloromethane.

In an alternate way, the compound of formula (If) can be prepared by theBoc deprotection of compounds of formula (Id-1) using similar conditionsas described in scheme-B.

Various compounds of formula (I) such as compounds of formula (Ig), (Ih)(Ii) and (Ij) can be prepared from the compound of formula (Ia) or (Ib),as shown in scheme D, wherein R, R₁, R₂, R₃, R_(3′), R₇, R_(7′), Y, z, mand n are as defined above.

The compound of formula (Ih) can be prepared by reacting the compound offormula (Ig) with appropriate amine using coupling reagent such ascarbodiimides, CDI or PyBop.

The compound of formula (Ij) can be prepared by alkaline hydrolysis ofcompound of formula (II) in the presence of base including alkalihydroxide such as sodium hydroxide and in inert solvent liketetrahydrofuran, water or mixture thereof.

The compound of formula (II) can be obtained by reacting compounds offormula (Ib) with sodium alkoxide such as sodium ethoxide in suitablesolvent such as tetrahydrofuran at room temperature.

The compound of formula (Ig) can be prepared by alkaline hydrolysis ofthe compound of formula (Ia).

Various compounds of formula (I), such as compounds of formula (Ik) canbe prepared as shown in scheme E, wherein R, R₁, R₂, R₃, R_(3′), Y, z, mand n are as defined above. The compounds belong to formula (Ik), whereP is —NH₂, —NHR₇, —NR₇R_(7′), NHOH and NHOR₇ can be obtained by couplingof formula (Ic) with appropriate amine in suitable condition such asusing coupling reagent such as carbodiimides in suitable aproticsolvent.

Further, compounds belong to formula (I), where P is NHSO₂R₇ and NHCOR₇can be obtained by coupling of formula (IV) or (III) or (Ic) withsuitable reagents and conditions.

A general synthetic method is provided for each of the disclosed groupsof chemical compounds. One of ordinary skill will recognize tosubstitute appropriately modified starting material containing thevarious substituents. One of ordinary skill will readily synthesize thedisclosed compounds according to the present invention usingconventional synthetic organic techniques and microwave techniques fromstarting material which are either purchased or may be readily preparedusing prior art methods.

The compounds of the present invention may have chiral centers and occuras racemates, racemic mixtures and as individual diastereomers orenantiomers with all isomeric forms being included in the presentinvention. Therefore, where a compound is chiral, the separateenantiomers, substantially free of the other, are included within thescope of the invention; further included are all mixtures of the twoenantiomers.

The novel compounds of the present invention are not, however, to beconstrued as forming the only genus that is considered as the invention,and any combination of the compounds or their moieties may itself form agenus.

The novel compounds of the present invention were prepared according tothe procedure of the schemes as described herein above, usingappropriate materials and are further exemplified by the followingspecific examples. The examples are not to be considered nor construedas limiting the scope of the invention set forth.

EXAMPLES Example-1 Preparation of[(2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid (Compound no. 1)

Step-1: Synthesis of2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carboxylicacid

The suspension of 4,5,6,7-tetrahydro-benzothiazol-2-yl-amine (8 gm,0.0519 mol) and5-(bis-ethylsulfanyl-methylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione(14.2 gm, 0.0572 mol) in ethanol (60 ml) was heated at 85-90° C. for 10hours. Reaction mixture was cooled to room temperature and filtered. Thesolid, thus obtained, was washed with ethanol (20 ml) followed by withdiethyl ether (50 ml) and suck dried to give 7.2 gm of title compound asa solid.

¹H-NMR (400 MHz, DMSO-d₆): δ 13.55 (1H, s), 3.30-3.34 (2H, m), 2.68-2.72(2H, m), 2.48 (3H, s), 1.88-1.92 (4H, m)

ESMS: 296.9 (M⁺+1)

Step-2: Synthesis of[(2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid ethyl ester

To the solution of acid compound as obtained in step-1 (7.0 gm, 0.0236mol) in dichloromethane (250 ml), triethylamine (9.85 ml, 0.070 mol) andglycine ethyl ester hydrochloride (4.93 gm, 0.0354 mol) were added atroom temperature. To the reaction mixture,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.81 gm,0.0354 mol) was added portion wise at 10-15° C. and was allowed to stirat room temperature for 14 hours. Dichloromethane was distilled offunder vacuum. To the residue, water (200 ml) was added and stirred for15 minutes. Solid, thus appeared, was filtered and washed with water. Itwas further slurred in mixture of ethyl acetate (20 ml) and diethylether (30 ml) and filtered. Solid, thus obtained, was suck dried to give6.2 gm title compound.

¹H-NMR (400 MHz, CDCl₃): δ 9.78 (1H, bs), 4.18-4.25 (4H, m), 3.31-3.36(2H, m), 2.64-2.69 (2H, m), 2.43 (3H, s), 1.85-1.90 (4H, m), 1.28 (3H,t)

ESMS: 382 (M⁺+1)

Step-3: Synthesis of[(2-methanesulfonyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid ethyl ester

To the cooled solution of ester compound as obtained in step-2 (6.0 gm,0.0157 mol) in dichloromethane (60 ml), a solution of m-chloroperbenzoic acid (50-60%, 8.13 gm) in dichloromethane (80 ml) was addedat 5-10° C. and stirred at same temperature for 1 hour. The reactionmixture was partitioned between dichloromethane and water. Collectedorganic layer was washed with sodium bicarbonate, dried over sodiumsulphate and distilled off under vacuum to give crude residue which waspurified by column chromatography using 1% methanol-dichloromethane. Thecollected fractions were evaporated to give 2.5 gm of title compound.

¹H-NMR (400 MHz, CDCl₃): δ 7.42 (1H, bs), 4.18-4.27 (4H, m), 3.36-3.37(2H, m), 3.33 (3H, s), 2.72-2.76 (2H, m), 1.87-1.91 (4H, m), 1.30 (3H,t)

ESMS: 413.9 (M⁺+1)

Step-4: Synthesis of[(2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]aceticacid

To the solution of sulfone derivative as obtained in step-3 (2.5 gm,0.006 mol) in tetrahydrofuran, a solution of sodium hydroxide (0.75 gm,0.0187 mol) in water (15 ml) was added and stirred at room temperaturefor 4 hours. Tetrahydrofuran was distilled under vacuum and theremaining solution was acidified by 1N hydrochloric acid and stirred for30 minutes. Solid, thus appeared, was filtered and washed with ethylacetate (25 ml) and dried under vacuum at 60° C. for 8 hours to give1.45 gm title compound as a solid.

¹H-NMR (400 MHz, DMSO-d₆): δ 9.70 (1H, t), 4.06 (2H, d), 3.15-3.21 (2H,m), 2.60-2.70 (2H, m), 1.76-1.80 (4H, m)

ESMS: 322 (M⁺−1)

IR (KBr, CM⁻¹): 3267.9, 1734.5, 1679.9

Example-2 Preparation of[(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[α]azulene-3-carbonyl)-amino]-aceticacid (Compound no. 10)

Step-1: Synthesis of2-methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[α]azulene-3-carboxylicacid

The title compound was prepared from5,6,7,8-tetrahydro-4H-cycloheptathiazol-2-yl-amine using similar methodas described for step-1 of example-1.

¹H-NMR (400 MHz, DMSO-d₆): δ 3.56-3.59 (2H, m), 2.82-2.85 (2H, m), 2.42(3H, s), 1.70-1.83 (6H, m)

ESMS: 310.9 (M⁺+1)

Step-2: Synthesis of[(2-methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[α]azulene-3-carbonyl)-amino]-aceticacid ethyl ester

The title compound was prepared using similar method as described forstep-2 of example-1.

¹H-NMR (400 MHz, CDCl₃): δ 9.78 (1H, bs), 4.19-4.25 (4H, m), 3.66-3.69(2H, m), 2.72-2.75 (2H, m), 2.42 (3H, s), 1.73-1.89 (6H, m), 1.27 (3H,t)

ESMS: 396 (M⁺+1)

Step-3: Synthesis of[(2-methanesulfonyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[α]azulene-3-carbonyl)-amino]-aceticacid ethyl ester

To the cooled solution of compound as obtained in step-2 (3.0 gm, 0.0076mol) in dichloromethane (60 ml), a solution of m-chloro perbenzoic acid(50-60%, 4.50 gm) in dichloromethane (60 ml) was added at 5-10° C. andstirred at same temperature for 3 hours. Dichloromethane (100 ml) wasadded to reaction mixture and partitioned between dichloromethane andwater. Organic layer was washed with sodium bicarbonate, dried oversodium sulphate and distilled off under vacuum to give crude residuewhich was stirred in diethyl ether (100 ml). The solid, thus obtained,was collected by filtration and suck dried to give 2.5 gm of titlecompound.

¹H-NMR (400 MHz, CDCl₃): δ 7.36 (1H, bs), 4.19-4.27 (4H, m), 3.68-3.71(2H, m), 3.33 (3H, s), 2.80-2.83 (2H, m), 1.78-1.91 (6H, m), 1.30 (3H,t)

ESMS: 428 (M⁺+1)

Step-4: Synthesis of[(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[α]azulene-3-carbonyl)-amino]-aceticacid

The title compound was prepared using similar method as described forstep-4 of example-1.

¹H-NMR (400 MHz, DMSO-d₆): M6.2 (1H, bs), 9.74 (1H, t), 4.06 (2H, d),3.55-3.60 (2H, m), 2.75-2.80 (2H, m), 1.70-1.84 (6H, m)

ESMS: 335.9 (M⁺−1)

IR (KBr, CM⁻¹): 3268.2, 1739.6, 1674.6

Example-3 Preparation of3-(carboxymethyl-carbamoyl)-2-hydroxy-4-oxo-5,8-dihydro-4H,6H-9-thia-1,4a,7-triaza-fluorene-7-carboxylicacidethylester (Compound no. 2)

Step-1: Synthesis of2-methylsulfanyl-4-oxo-5,8-dihydro-4H,6H-9-thia-1,4a,7-triaza-fluorene-3,7-dicarboxylicacid 7-ethyl ester

The title compound was prepared from2-amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid ethylester using similar method as described for step-1 of example-1

¹H-NMR (400 MHz, DMSO-d₆): δ 13.52 (1H, s), 4.60 (2H, bs), 4.09 (2H, q),3.69 (2H, bs), 3.27 (2H, bs), 2.43 (3H, s), 1.22 ((3H, t)

ESMS: 370.1 (M⁺+1)

Step-2: Synthesis of3-(ethoxycarbonylmethyl-carbamoyl)-2-methylsulfanyl-4-oxo-5,8-dihydro-4H,6H-9-thia-1,4a,7-triaza-fluorene-7-carboxylicacid ethyl ester

The title compound was prepared using similar method as described forstep-2 of example-1.

¹H-NMR (400 MHz, DMSO-d₆): δ 9.50 (1H, t), 4.58 (2H, bs), 4.03-4.15 (6H,m), 3.67 (2H, t), 3.24-3.34 (2H, partially overlapped by water signal),2.34 (3H, s), 1.18-1.23 (6H, m)

ESMS: 455.2 (M⁺+1)

Step-3: Synthesis of3-(ethoxycarbonylmethyl-carbamoyl)-2-methanesulfonyl-4-oxo-5,8-dihydro-4H,6H-9-thia-1,4a,7-triaza-fluorene-7-carboxylicacid ethyl ester

The title compound was prepared using similar method as described forstep-3 of example-2.

¹H-NMR (400 MHz, DMSO-d₆): δ 8.59 (1H, t), 4.62-4.68 (2H, m), 4.02-4.15(4H, m), 3.97 (2H, d), 3.65-3.70 (2H, m), 3.34 (2H, hidden under watersignal), 3.23 (3H, s), 1.18-1.28 (6H, m)

ESMS: 487.2 (M⁺+1)

Step-4: Synthesis of3-(carboxymethyl-carbamoyl)-2-hydroxy-4-oxo-5,8-dihydro-4H,6H-9-thia-1,4a,7-triaza-fluorene-7-carboxylicacid ethyl ester

The title compound was prepared using similar method as described forstep-4 of example-1.

¹H-NMR (400 MHz, DMSO-d₆): δ 16.24 (1H, s), 12.9 (1H, bs), 9.66 (1H, t),4.55 (2H, bs), 4.07-4.11 (4H, m), 3.67 (2H, t) 3.23-3.35 (2H, partiallyoverlapped by water signal), 1.21 (3H, t)

ESMS: 395 (M⁺−1)

IR (KBr, CM⁻¹): 3260.2, 1741, 1672.8

Example-4 Preparation of{[2-hydroxy-4-oxo-7-(5-trifluoromethyl-pyridin-2-yl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid (Compound no. 18)

Step-1: Synthesis of(5-(5-trifluoromethyl-pyridin-2-yl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine)

The mixture of 1-(5-trifluoromethyl-pyridin-2-yl)-piperidine-4-one (9.9gm, 0.0405 mol), pyrrolidine (3.53 ml, 0.0445 mol) and p-toluenesulfonicacid (100 mg) in cyclohexane (50 ml) were refluxed for 3 hours and waterwas removed with Dean-Stark apparatus. The resultant mixture wasconcentrated under reduced pressure, and the residue was dissolved inmethanol (100 ml). Sulfur powder (1.05 gm, 0.0405 mol) and cynamide(1.37 gm, 0.0405 mol) were added to the solution and stirred at roomtemperature for overnight. The resultant solid was collected byfiltration and washed with methanol (10 ml) to give 6.0 gm of titlecompound.

¹H-NMR (400 MHz, DMSO-d₆): δ 8.43 (1H, s), 7.82 (1H, dd), 7.04 (1H, d),6.82 (2H, s), 4.62 (2H, s), 3.96 (2H, t), 2.55 (2H, t)

ESMS: 301 (M⁺+1)

Step-2: Synthesis of2-hydroxy-4-oxo-7-(5-trifluoromethyl-pyridin-2-yl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carboxylicacid ethyl ester

The mixture of5-(5-trifluoromethyl-pyridin-2-yl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine(5.7 gm, 0.019 mol) and triethyl methanetricarboxylate (16.1 ml, 0.076mol) in xylene (100 ml) was heated at 140-150° C. for 6 hours. Xylenewas evaporated and diethyl ether was then added and the suspension wasstirred for 15 minutes. It was filtered and washed with ether. The crudesolid was digested with dichloromethane (200 ml) and filtered to removeinsoluble residue. Dichloromethane layer was distilled off under vacuumto give 1.3 gm of title compound.

¹H-NMR (400 MHz, CDCl₃): δ 13.96 (1H, s), 8.44 (1H, s), 7.72 (1H, dd),6.79 (1H, d), 4.80 (2H, s), 4.47 (2H, q), 3.94 (2H, t), 3.53-3.56 (2H,m), 1.44 (3H, t)

ESMS: 440.9 (M⁺+1)

Step-3: Synthesis of{[2-hydroxy-4-oxo-7-(5-trifluoromethyl-pyridin-2-yl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid ethyl ester

The mixture of compound as obtained in step-2 (1.2 gm, 0.0272 mol) withglycine ethyl ester hydrochloride (0.42 gm, 0.0030 mol) was heated indry pyridine (10 ml) at 100° C. for 5 hours. Pyridine was evaporated todryness and residue was stirred in diethyl ether (50 ml). The solid,thus obtained, was collected by filtration and washed by ethanol (10 ml)and diethyl ether (10 ml). It was suck dried to give 260 mg of titlecompound.

¹HNMR (400 MHz, CDCl₃): δ 15.99 (1H, s), 9.74 (1H, t), 8.45 (1H, s),7.72 (1H, dd), 6.79 (1H, d), 4.80 (2H, s), 4.18-4.26 (4H, m), 3.97 (2H,t), 3.53 (2H, t), 1.30 (3H, t)

ESMS: 498 (M⁺+1)

Step-4: Synthesis of{[2-hydroxy-4-oxo-7-(5-trifluoromethyl-pyridin-2-yl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid

The title compound was prepared using similar method as described forstep-4 of example-1.

¹H-NMR (400 MHz, DMSO-d₆): δ 9.67 (1H, t), 8.48 (1H, s), 7.91 (1H, dd),7.14 (1H, d), 4.85 (2H, s), 4.07 (2H, d), 4.01 (2H, t), 3.34 (2H, hiddenunder signal of water)

ESMS: 467.9 (M⁺−1)

IR (KBr, CM⁻¹): 3292.7, 1725.7, 1677.7

Example-5 Preparation of{[7-(5-chloro-thiophene-2-sulfonyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid (Compound no. 17)

Step-1: Synthesis of2-methylsulfanyl-4-oxo-5,8-dihydro-4H,6H-9-thia-1,4a,7-triaza-fluorene-3,7-dicarboxylicacid 7-tert-butyl ester

The title compound was prepared from2-amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acidtert-butyl ester using similar method as described for step-1 ofexample-1.

¹H-NMR (400 MHz, CDCl₃): δ 13.38 (1H, bs), 4.56 (2H, bs), 3.76 (2H, t)3.42 (2H, bs), 2.49 (3H, s), 1.50 (9H, s)

ESMS: 398.2 (M⁺+1)

Step-2: Synthesis of3-(ethoxycarbonylmethyl-carbamoyl)-2-methylsulfanyl-4-oxo-5,8-dihydro-4H,6H-9-thia-1,4a,7-triaza-fluorene-7-carboxylicacid tert-butyl ester

The title compound was prepared using similar method as described forstep-2 of example-1.

¹H-NMR (400 MHz, CDCl₃): δ 9.71 (1H, t), 4.52 (2H, bs), 4.18-4.25 (4H,m), 3.72 (2H, t) 3.37-3.44 (2H, m), 2.43 (3H, s), 1.50 (9H, s), 1.27(3H, t)

ESMS: 483.2 (M⁺+1)

Step-3: Synthesis of[(2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-aceticacid ethyl ester

To the solution of N-Boc derivative as obtained in step-2 (19.0 gm,0.0394 mol) in dichloromethane (60 ml), trifluoroacetic acid (60 ml) wasadded over 0.5 hour at 0-5° C. and stirred at room temperature for 4hours. Solvent were distilled under vacuum and water (100 ml) was added.It was basified with sodium bicarbonate solution and resulted solid wascollected by filtration. Solid was further washed by diethyl ether (50ml) and dried under vacuum at 60° C. for 6 hours to give 11.0 gm oftitle compound.

¹H-NMR (400 MHz, CDCl₃): δ 9.74 (1H, bs), 4.18-4.25 (4H, m), 3.94 (2H,s), 3.34-3.37 (2H, m), 3.17 (2H, t), 2.43 (3H, s), 1.28 (3H, t)

ESMS: 382.9 (M++1)

Step-4: Synthesis of{[7-(5-chloro-thiophene-2-sulfonyl)-2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid ethyl ester

To the mixture of amine derivative as obtained in step-3 (1.0 gm, 0.0026mol) and pyridine (0.31 ml, 0.0039 mol) in dichloromethane, a solutionof 5-chloro-thiophene-2-sulfonyl chloride (0.62 gm, 0.00287 mol) indichloromethane (5 ml) was added at 0-5° C. and stirred at roomtemperature for 4 hours. Reaction mixture was poured into water (50 ml)and extracted with dichloromethane (50 ml×2). The combined organic layerwas dried over sodium sulphate and distilled off under vacuum to yield asolid, which was slurred in ethylacetate (10 ml). It was filtered andsuck dried to give 980 mg of title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ 9.42-9.48 (1H, m), 7.68 (1H, d), 7.39 (1H,d), 4.32-4.36 (2H, m), 4.02-4.13 (4H, m), 3.38-3.51 (4H, hidden undersignal of water), 2.34-2.36 (3H, m), 1.15-1.22 (3H, m)

ESMS: 564.8 (M⁺+1)

Step-5:{[7-(5-Chloro-thiophene-2-sulfonyl)-2-methanesulfonyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid ethyl ester

To the cooled solution of compound as obtained in step-4 (950 mg, 0.0017mol) in dichloromethane (20 ml), a solution of m-chloro perbenzoic acid(50-60%, 0.72 gm) in dichloromethane (30 ml) was added at 5-10° C. andstirred at room temperature for 2 hours. Reaction mixture was pouredinto water (100 ml) and extracted with dichloromethane (50 ml×2).Organic layer was washed with sodium bicarbonate, dried over sodiumsulphate and distilled off under vacuum to give 800 mg as a crude solid,which was used for next step without purification.

Step-6: Synthesis of{[7-(5-chloro-thiophene-2-sulfonyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid

A mixture of compound as obtained in step 5 (0.8 g, 0.0013 mol) intetrahydrofuran (20 ml), a solution of sodium hydroxide (160 mg, 0.004mol) in water (20 ml) was added. The reaction mixture was stirred atroom temperature for 2 hours. Solvent was distilled off under vacuum andremaining mass was acidified with dilute hydrochloric acid andprecipitate was appeared, which was collected by filtration and washedwith diethyl ether (40 ml). Solid was dried under vacuum to give 220 mgof title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ 16.28 (1H, s), 12.9 (1H, bs), 9.64 (1H, t),7.65 (1H, d), 7.39 (1H, d), 4.30-4.40 (2H, m), 4.08 (2H, d), 3.40-3.50(2H, m), 3.34 (2H, hidden under signal of water)

ESMS: 502.9 (M⁺−1)

IR (KBr, CM⁻¹): 3304.8, 1714.3, 1682.3

Example-6 Preparation of2-Methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylicacid (2-oxo-2-pyrrolidin-1-yl-ethyl)-amide (Compound no. 79)

Step-1: Synthesis of[(2-Methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid

The title compound was prepared using similar hydrolysis conditions asdescribed for step-4 of example-1 starting from[(2-methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid ethyl ester (step-2 of example-2).

¹H-NMR (400 MHz, DMSO-d₆): δ 9.50 (1H, t), 3.97 (2H, d), 3.58-3.61 (2H,m), 2.79-2.81 (2H, m), 2.32 (3H, s), 1.81-1.82 (2H, m), 1.70-1.71 (4H,m)

ESMS: 368.1 (M⁺1+1)

Step-2: Synthesis of2-Methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylicacid (2-oxo-2-pyrrolidin-1-yl-ethyl)-amide

To the stirred solution of compound obtained in step-1 (1.0 gm, 0.0027mole) in dichloromethane (20 ml), triethylamine (1.13 ml, 0.0082 mole)and pyrrolidine (0.29 gm, 0.0040 mole) were added. To the reactionmixture, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.78 gm, 0.0040 mole) was added and stirred at room temperature for 12hrs. Organic layer was washed with 1N hydrochloric acid (50 ml) andsodium bicarbonate solution. Organic solvent was distilled off to yielda solid, which was stirred in methanol (20 ml), filtered and suck driedto give 0.35 gm of title compound.

¹H-NMR (400 MHz, CDCl₃): δ 10.07 (1H, bs), 4.18 (2H, d), 3.69-3.71 (2H,m), 3.53 (2H, t), 3.42 (2H, t), 2.70-2.73 (2H, m), 2.41 (3H, s),1.96-2.04 (2H, m), 1.75-1.90 (8H, m)

ESMS: 421.1 (M⁺+1)

IR (KBr, CM⁻¹): 3297.3, 1650.9, 1601.8

Example-7 Preparation of[(2-Ethoxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid (Compound no. 81)

Step-1: Synthesis of[(2-Ethoxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid ethyl ester

The mixture of compound obtained in step-3 of example-2 (1.00 gm, 0.0023mole) and sodium ethoxide (0.318 gm, 0.0046 mole) in ethanol (20 ml) wasstirred at 80° C. for 15 min and then 10 hr at room temperature. Thereaction mixture was poured into 1N HCl and extracted with ethyl acetate(50 ml×2). Ethyl acetate was distilled off and crude residue waspurified using 20% ethyl acetate in hexane. The fractions were distilledoff to give 150 mg of title compound.

¹H-NMR (400 MHz, CDCl₃): δ 9.20 (1H, t), 4.49 (2H, q), 4.18-4.24 (4H,m), 3.65-3.68 (2H, m), 2.70-2.73 (2H, m), 1.78-1.88 (6H, m), 1.43 (3H,t), 1.26 (3H, t)

ESMS: 394.1 (M⁺+1)

Step-2: Synthesis of[(2-Ethoxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]aceticacid

The title compound was prepared using similar hydrolytic condition asdescribed for step-4 of example-1.

¹H-NMR (400 MHz, DMSO-d₆): δ 12.50 (1H, bs), 8.61 (1H, t), 4.34 (2H, q),3.88 (2H, d), 3.59-3.61 (2H, m), 2.76-2.79 (2H, m), 1.68-1.81 (6H, m),1.27 (3H, t)

ESMS: 364.3 (M⁺−1)

IR (KBr, CM⁻¹): 3316.2, 1711.9, 1655.8

Example-8 Preparation of2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylicacid cyclohexylcarbamoylmethyl-amide (Compound No. 98)

To the stirred suspension of[(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid (0.70 gm, 0.0020 mole) in dichloromethane (20 ml), triethylamine(0.85 ml, 0.0062 mole) and cyclohexylamine (0.29 ml, 0.0025 mole) wereadded. To the reaction mixture, hydroxybenzotriazole (0.28 gm, 0.0020mole) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.60 gm, 0.0031 mole) were added and stirred at room temperature for 12hrs. Dichloromethane was distilled off and 1N hydrochloric acid (50 ml)was added to the residue, the separated solid was collected byfiltration. The solid thus obtained was stirred in methanol (20 ml) at60° C. for 0.5 hr, filtered and suck dried to give 0.60 gm titlecompound.

¹1′-NMR (400 MHz, CDCl₃): δ 15.74 (1H, s), 9.94 (1H, t), 5.86 (1H, d),4.05 (2H, d), 3.75-3.82 (1H, m), 3.63-3.65 (2H, m), 2.69-2.72 (2H, m),1.78-1.93 (8H, m), 1.66-1.71 (2H, m), 1.58-1.61 (2H, m), 1.34-1.37 (2H,m), 1.14-1.16 (2H, m).

ESMS: 417.2 (M⁺−1)

IR (KBr, CM⁻¹): 2929.3, 1671.4, 1653.4

The following representative compounds of the present invention wereprepared in analogues manner by using the synthetic schemes as describedabove:

TABLE 1 Comp. No. ¹H-NMR (400 MHz, DMSO-d₆) MASS IR (KBr, CM⁻¹) 3 δ16.27 (1H, s), 12.9 (1H, bs), 9.67 (1H, t), 403.1 (M⁺ + 1) IR (KBr,CM⁻¹): 3263.9, 4.38-4.43 (2H, m), 4..08 (2H, d), 3.52 (2H, bs), 3.34(2H, 1746.3, 1625.3 hidden under signal of water) 3.01 (3H, s) 4 δ 16.26(1H, s), 12.9 (1H, bs), 9.67 (1H, t), 409.1 (M⁺ + 1) IR (KBr, CM⁻¹):4..61-4.68 (2H, m), 4.07-4..08 (2H, m), 3..76 (2H, t), 3289.2, 1731.6,1677.1 3.28-3.34 (2H, partailly overlapped by water signal) 2.25-2.33(2H, m), 1.98-2.04 (1H, m), 0.90-0.93 (6H, m) 5 δ 16.26 (1H, s), 12.9(1H, bs), 9.67 (1H, t), 431.1 (M⁺ + 1) IR (KBr, CM⁻¹): 4..46-4.50 (2H,m), 4.08 (2H, d), 3.61 (2H, t), 3.34-3.50 (3H, 3302.8, 1717.7, 1682.6partailly overlapped by water signal), 1.25 (6H, d) 6 δ15.98 (1H, s),12.7 (1H, bs), 9.81 (1H, s), 376.1 (M⁺ − 1) IR (KBr, CM⁻¹): 3.15-3.25(2H, m), 2.60-2.68 (2H, m), 2.15-2.25 (2H, m), 3228.9, 1732.3, 1631.21.90-2.00 (2H, m), 1.68-1.80 (8H, m) 7 δ 12.9 (1H, bs), 9.62 (1H, t),7.71 (2H, d), 7.45 (2H, d), 479.1 (M⁺ + 1) IR (KBr, CM⁻¹): 4..24 (2H,s), 4.07 (2H, d), 3.24-3.33 (4H, partailly 3307.2, 1716.9, 1640.8overlapped by water signal), 2.38 (3H, s) 8 δ12.9 (1H, bs), 9.68 (1H,t), 8.79 (1H, s), 441.9 (M⁺ − 1) IR (KBr, CM⁻¹): 7.45-7.47 (2H, m), 7.25(2H, t), 6.96 (1H, t), 4..61-4.91 (2H, m), 3273.8, 1736.9, 1680.9 4.09(2H, d), 3.79 (2H, bs), 3.30-3.40 (2H, hidden under signal of water) 9 δ16.22 (1H, s), 9.67 (1H, t), 4..61-4.91 (2H, m), 390.9 (M⁺ − 1) IR (KBr,CM⁻¹): 3.77-4.09 (4H, m), 3.34 (2H, hidden under signal of water),3280.4, 1728.0, 1673.7 1.95-2.14 (1H, m), 0.79 (4H, m) 11 δ 16.11 (1H,bs), 9.69 (1H, t), 4.08 (2H, d), 3.21 (2H, t), 308.0 (M⁺ − 1) IR (KBr,CM⁻¹): 2.84 (2H, t), 2.38-2.42 (2H, m) 3241.2, 1731.0, 1674.5 12 δ9.97(1H, t), 3.44 (2H, d), 3.04-3.12 (2H, m), 322.2 (M⁺ − 1) IR (KBr, CM⁻¹):2.46 (2H, partailly overlapped by solvent signal), 2941.5, 1648.1,1555.9 1.65-1.80 (4H, m), 13 δ 9.70 (1H, t), 4..07 (2H, d), 3.47-3.51(1H, m),   378 (M⁺ − 1) IR (KBr, CM⁻¹): 2.80-3.00 (1H, m), 2.62-2.78(1H, m), 2.35-2.42 (1H, m), 3277.9, 1739.8, 1684.3 1.95-2.10 (1H, m),1.40-1.55 (1H, m), 1.25-1.35 (1H, m), 0.92 (9H, s) 14 δ 16.43 (1H, s),12.39 (1H, s), 9.58 (1H, t), 321.9 (M⁺ − 1) IR (KBr, CM⁻¹): 3.54 (2H,q), 3.19 (2H, t), 2.82 (2H, t), 2.50-2.55 (2H, 3292.5, 1722.0, 1680.3partailly overlapped by solvent signal), 2.35-2.45 (2H, m) 15 ¹H-NMR(400 MHz, CDCl₃) 394.1 (M⁺ + 1) IR (KBr, CM⁻¹): δ 16.21 (1H, s), 9.67(1H, s), 3.68-3.72 (2H, m), 3289.6, 1721.8, 1635.6 3.55-3.60 (1H, m),2.90-3.10 (1H, m), 2.60-2.74 (3H, m), 2.35-2.45 (1H, m), 2.05-2.15 (1H,m), 1.45-1.60 (1H, m), 1.30-1.40 (1H, m) 0.95 (9H, s) 16 δ 16.24 (1H,bs), 9.67 (1H, t), 7.55-7.58 (2H, m), 444.9 (M⁺ − 1) IR (KBr, CM⁻¹):7.32 (2H, t), 4.60-4.80 (2H, m), 4..09 (2H, d), 3257.1, 1725.7, 1668.13.80-3.90 (1H, bs), 3.55-3.65 (1H, bs), 3.35 (2H, hidden under signal ofwater) 19 δ 9.63 (1H, t), 7.98 (2H, d), 7.62 (2H, d), 4.30 (2H, bs),546.9 (M⁺ − 1) IR (KBr, CM⁻¹): 3.98 (2H, d), 3.47-3.50 (2H, m, partaillyoverlapped 3289.5, 1739.7, 1673.8 by water signal), 3.23-3.33 (2H,hidden under signal of water) 20 δ 9.67 (1H, t), 4.68 (2H, bs), 4.08(2H, d), 3.85 (2H, t),   407 (M⁺ − 1) IR (KBr, CM⁻¹): 3.34 (2H, hiddenunder signal of water), 1.23 (9H, s) 3275.9, 1740.4, 1673.8 21 δ 16.24(1H, s), 9.68 (1H, t), 7.40 (2H, d), 7.31 (2H, d), 483.1 (M⁺ − 1) IR(KBr, CM⁻¹): 4.60-4.80 (2H, bs), 4.09 (2H, d), 3.50-3.80 (2H, m),3268.1, 1729.5, 1683.3 3.37 (2H, hidden under signal of water), 2.63(2H, t) 1.58 (2H, m), 1.32-1.40 (2H, m), 0.91 (3H, t) 22 δ 9.69 (1H, t),7.64 (2H, d), 7.48 (2H, d),   511 (M⁺ − 1) IR (KBr, CM⁻¹): 4.58-4.75(2H, m), 3.76-4.03 (4H, m), 3.35-3.65 (2H, 3272.1, 1725.4, 1683.7partailly overlapped by water signal)) 23 δ 16.19 (1H, bs), 9.68 (1H,t), 7.37-7.42 (4H, m),   447 (M⁺ − 1) IR (KBr, CM⁻¹): 4.07 (2H, d), 3.70(2H, s), 3.46-3.54 (2H, m), 3263.7, 1732.1, 1682.7 3.20-3.33 (2H,partailly overlapped by water signal), 2.80 (2H, t) 24 δ 9.63-9.69 (2H,m), 7.30-7.34 (2H, m), 7.16 (2H, t),   476 (M⁺ − 1) IR (KBr, CM⁻¹): 5.10(2H, bs), 4.16 (2H, t), 4.06 (2H, d), 3267.2, 1720.3, 1681.8 3.34-3.50(2H, partailly overlapped by water signal) 25 δ 16.2 (1H, bs) 9.67 (1H,t), 7.63 (1H, d), 5.00 (2H, s),   424 (M⁺ − 1) IR (KBr, CM⁻¹): 4.52-4.54(1H, m), 4.02-4.10 (4H, m), 3.34 (2H, hidden 3266.4, 1718.4, 1681.3under signal of water), 1.17 (6H, d) 26 δ 16.26 (1H, bs) 9.67 (1H, t),7.33-7.40 (5H, m),   457 (M⁺ − 1) IR (KBr, CM⁻¹): 5.15 (2H, s), 4.59(2H, bs), 4.07 (2H, d), 3.72 (2H, bs), 3282.0, 1676.2, 1564.9 3.33 (2H,hidden under signal of water) 27 δ 16.2 (1H, bs) 9.67 (1H, t), 4.61-4.64(2H, m), 405.1 (M⁺ − 1) IR (KBr, CM⁻¹): 4.08 (2H, d), 3.72-3.76 (2H, m),3.20-3.31 (2H, partailly 3300.5, 1728.2, 1677.8 overlapped by watersignal), 2.32-2.40 (2H, m), 0.98-1.08 (1H, m), 0.45-0.47 (2H, m),0.13-0.15 (2H, m), 28 δ 9.66 (1H, t), 7.24-7.39 (4H, m), 4.62-4.72 (2H,m), 475.1 (M⁺ − 1) IR (KBr, CM⁻¹): 4.08 (2H, d), 3.75-3.86 (4H, m),3.20-3.30 (2H, m), 3287.9, 1731.1, 1675.3 29 δ 16.21 (1H, bs), 12.9 (1H,bs), 9.67 (1H, t), 433.0 (M⁺ − 1) IR (KBr, CM⁻¹): 4.60-4.67 (2H, m),4.08-4.09 (2H, m), 3.75 (2H, t), 3304.6, 1731.2, 1675.7 3.15-3.31 (2H,partailly overlapped by water signal), 2.39-2.47 (2H, m, partaillyoverlapped by solvent signal), 2.14-2.16 (1H, m), 1.73-1.77 (2H, m),1.40-1.60 (4H, m), 1.00-1.20 (2H, m) 30 δ 12.5 (1H, bs), 9.66 (1H, t),3..51-3.54 (4H, m),   352 (M⁺ + 1) IR (KBr, CM⁻¹): 2.72-2.80 (2H, m),2.50-2.55 (2H, partailly overlapped by 3198.0, 1731.9, 1670.1 solventsignal), 1.60-1.85 (6H, m) 31 δ 9.69 (1H, bs), 7.27 (2H, d), 6.91 (2H,d), 443.2 (M⁺ − 1) IR (KBr, CM⁻¹): 4.06 (2H, d), 3.75 (3H, s), 3.64 (2H,bs), 3.49 (2H, bs), 3259.2, 1678.9, 1611.6 3.24 (2H, partaillyoverlapped by water signal), 2.78 (2H, bs) 32 δ 16.09 (1H, bs), 13.1(1H, bs), 9.87 (1H, d), 349.8 (M⁺ − 1) IR (KBr, CM⁻¹): 4.46-4.49 (1H,m), 3.55-3.65 (2H, m), 2.70-2.80 (2H, m), 3261.1, 1736.2, 1684.01.77-1.85 (2H, m), 1.65-1.75 (4H, m), 1.42 (3H, d) 33 δ 9.69 (1H, t),8.56 (1H, s), 7.99 (1H, bs) 7.66 (1H, d), 461.9 (M⁺ − 1) IR (KBr, CM⁻¹):4.62-4.76 (2H, m), 4.03 (2H, d), 3.80-3.95 (2H, m) 3262.6, 1634.1,1538.8 3.36-3.65 (2H, partailly overlapped by water signal), 34 δ 16.17(1H, s), 9.72 (1H, t), 4.08 (2H, d), 3.19 (2H, t), 349.9 (M⁺ − 1) IR(KBr, CM⁻¹): 2.44 (2H, s), 1.57 (2H, t), 1.00 (6H, s) 3256.9, 1718.7,1680.8 35 δ 16.24 (1H, bs), 9.67 (1H, t), 7.65 (1H, d), 434.9 (M⁺ − 1)IR (KBr, CM⁻¹): 7.57 (1H, d), 4.83 (2H, bs), 4.08 (2H, d), 3.96 (2H, t),3300.7, 1716.5, 1679.7 3.34 (2H, hidden under signal of water) 36 δ16.26 (1H, bs), 9.69 (1H, t), 8.45 (1H, dd), 426.8 (M⁺ + 1) IR (KBr,CM⁻¹): 8.17 (1H, dd), 7.02 (1H, dd), 4.72 (2H, s), 4.07 (2H, d), 3375.9,1718.6, 1675.7 3.94 (2H, t), 3.35-3.46 (2H, partailly overlapped bywater signal) 37 δ 16.25 (1H, s), 9.67 (1H, t), 7.56 (1H, d), 7.46 (1H,dd), 490.8 (M⁺ − 1) IR (KBr, CM⁻¹): 7.24 (1H, d), 4.68 (2H, bs), 4.09(2H, d), 3.91 (3H, s), 3376.0, 1702.0, 1647.0 3.34 (4H, hidden undersignal of water) 38 δ 16.20 (1H, s), 9.76 (1H, t), 4.08 (2H, d), 3.34(2H, 350.0 (M⁺ − 1) IR (KBr, CM⁻¹): hidden under signal of water),2.80-2.82 (2H, m), 3267.8, 1736.2, 1677.8 1.72.1.74 (2H, m), 1.61-1.63(2H, m), 1.49-1.51 (2H, m), 1.32-1.35 (2H, m) 39 ¹H-NMR (400 MHz,CDCl₃): δ 16.04 (1H, bs), 453.1 (M⁺ − 1) IR (KBr, CM⁻¹): 9.74 (1H, bs),7.08-7.26 (3H, m), 4.16-4.18 (2H, m), 3295.0, 1674.8, 1633.3 3.73-3.75(2H, m), 3.52-3.54 (2H, m), 3.39-3.41 (2H, m), 2.88-2.92 (6H, m),2.06-2.10 (2H, m) 40 δ 16.05 (1H, s), 9.86 (1H, d), 4.47-4.49 (1H, m),364.2 (M⁺ − 1) IR (KBr, CM⁻¹): 3.19 (2H, t), 2.44 (2H, s), 1.56 (2H, t),1.42 (3H, d), 3254.2, 1738.1, 1533.3 1.00 (6H, s) 41 δ 9.67 (1H, bs),6.59-6.61 (3H, m), 4.58-4.73 (2H, m), 480.0 (M⁺ + 1) IR (KBr, CM⁻¹):4.06 (2H, d), 3.87-3.88 (m, 2H), 3.77 (6H, s), 3065.4, 1725.1, 1629.63.36-3.65 (2H, partailly overlapped by water signal), 42 δ 16.25 (1H,s), 9.67 (1H, t), 8.02 (2H, d), 7.75 (2H, d), 505.0 (M⁺ − 1) IR (KBr,CM⁻¹): 4.79 (1.2H, bs), 4.54 (0.8H, bs), 4.09 (2H, d), 3284.4, 1742.8,1685.0 3.95 (0.8H, bs), 3.57 (1.2H, bs), 3.34 (2H, hidden under signalof water), 3.28 (3H, s), 43 δ 16.00 (1H, s), 9.89 (1H, d), 4.44-4.45(1H, m), 392.2 (M⁺ − 1) IR (KBr, CM⁻¹): 3.20 (2H, t), 2.44 (2H, s),2.19-2.23 (1H, m), 1.56 (2H, t), 3261.2, 1736.1, 1682.0 1.00 (6H, s),0.92-0.95 (6H, m) 44 δ 16.04 (1H, s), 9.85 (1H, d), 4.47-4.50 (1H, m),366.0 (M⁺ + 1) IR (KBr, CM⁻¹): 3.19 (2H, t), 2.44 (2H, s), 1.56 (2H, t),1.42 (3H, d), 3265.3, 1738.3, 1689.8 1.00 (6H, s) 45 δ 9.70 (1H, bs),7.63 (2H, s), 4.60-4.72 (2H, m), 526.9 (M⁺ − 1) IR (KBr, CM⁻¹): 4.01(2H, d), 3.77-3.88 (5H, m) 3.35-3.60 (2H, partailly 3255.7, 1741.6,1673.2 overlapped by water signal) 46 δ 9.74 (1H, bs), 8.04-8.07 (3H,m), 3.91-3.93 (4H, m), 549.2 (M⁺ − 1) IR (KBr, CM⁻¹): 3.59-3.61 (2H, m)3.35 (2H, merged with water 3267.6, 1731.4, 1679.5 signal), 2.86 (2H, t)47 δ 9.67 (1H, bs), 7.40 (2H, d), 7.30 (2H, d), 469.1 (M⁺ − 1) IR (KBr,CM⁻¹): 4.70 (2H, bs), 4.08 (2H, d), 3.62-3.90 (2H, m), 3.34 (2H, 3270.1,1742.6, 1683.5 merged with water signal), 2.61 (2H, t), 1.57-1.66 (2H,m), 0.91 (3H, t) 48 δ 9.67 (1H, t), 8.22-8.28 (3H, m), 4.79 (1H, bs),563.1 (M⁺ − 1) IR (KBr, CM⁻¹): 4.57 (1H, bs), 4.07 (2H, d), 3.95 (1H,bs), 3.57-3.36 (3H, 3269.7, 1722.9, 1691.7 partailly overlapped by watersignal) 49 δ 9.69 (1H, t), 7.61-7.63 (2H, m), 7.37 (1H, dd), 481.1 (M⁺− 1) IR (KBr, CM⁻¹): 4.05 (2H, d), 3.72 (2H, s), 3.54 (2H, bs) 3.26 (2H,partailly 3247.9, 1733.0, 1684.3 overlapped by water signal), 2.82 (2H,t) 52 δ 9.79 (1H, bs), 7.72 (2H, d), 7.59 (2H, d), 482.9 (M⁺ + 1) IR(KBr, CM⁻¹): 3.81 (2H, bs), 3.76 (2H, d), 3.38-3.52 (2H, partailly3279.6, 1734.1, 1681.1 overlapped by water signal), 3.26-3.38 (2H,partailly overlapped by water signal), 2.83 (2H, t) 53 δ 16.13 (1H, s),9.71 (1H, t), 4.08 (2H, d), 3.14 (2H, t), 380.0 (M⁺ + 1) IR (KBr, CM⁻¹):2.43 (2H, s), 1.59 (2H, t), 1.30-1.37 (4H, m), 3227.6, 1741.8, 1676.60.80 (6H, t) 54 δ 16.05 (1H, s), 9.95 (1H, s), 3.18 (2H, t), 378.2 (M⁺− 1) IR (KBr, CM⁻¹): 2.44 (2H, s), 1.53-1.56 (8H, m), 1.00 (6H, s)3228.7, 1730.4, 1688.6 55 δ 15.81 (1H, bs), 10.38 (1H, d), 7.32-7.41(5H, m), 428.0 (M⁺ + 1) IR (KBr, CM⁻¹): 5.50 (1H, d), 3.20 (2H, t), 2.44(2H, s), 1.56 (2H, t), 29.8.0, 1732.1, 1683.7 1.0 (6H, s) 56 δ 16.22(1H, s), 9.72 (1H, t), 8.50 (1H, d), 441.1 (M⁺ − 1) IR (KBr, CM⁻¹):7.84-7.85 (2H, m), 7.47-7.54 (3H, m), 4.25-4.35 (1H, m), 3323.0, 1733.9,1670.7 4.09 (2H, d), 3.35-3.50 (1H, partailly overlapped by watersignal), 3.10-3.35 (1H, partailly overlapped by water signal), 2.95-3.05(1H, m), 2.60-2.70 (1H, m), 2.00-2.10 (1H, m), 1.85-1.95 (1H, m) 57 δ16.39 (1H, s), 9.64 (1H, t), 4.08 (2H, d), 306.3 (M⁺ − 1) IR (KBr,CM⁻¹): 2.93-2.94 (2H, m), 2.60-2.62 (2H, m), 1.78-1.82 (4H, m), 3251.2,1736.7, 1676.9 58 δ 16.18 (1H, s), 9.71 (1H, t), 4.08 (2H, d), 3.34 (1H,336.1 (M⁺ − 1) IR (KBr, CM⁻¹): merged with water signal), 2.90-3.10 (1H,m), 3256.9, 1733.5, 1674.4 2.72-2.80 (1H, m), 2.20-2.30 (1H, m),1.85-1.95 (2H, m), 1.40-1.50 (1H, m), 1.04 (3H, d), 59 δ 16.16 (1H, s),9.70 (1H, t), 4.08 (2H, d), 364.1 (M⁺ − 1) IR (KBr, CM⁻¹): 3.34-3.40(1H, partailly overlapped by water signal), 3278.8, 1732.3, 1674.72.90-3.10 (1H, m), 2.70-2.80 (1H, m), 2.20-2.30 (1H, m), 1.85-1.95 (1H,m), 1.60-1.70 (1H, m), 1.30-1.40 (5H, m), 0.90 (3H, t) 60 δ 16.16 (1H,s), 9.72 (1H, t), 4.07 (2H, d), 3.01 (2H, s), 350.1 (M⁺ − 1) IR (KBr,CM⁻¹): 2.65 (2H, t), 1.56 (2H, t), 1.00 (6H, s) 3267.9, 1745.4, 1682.461 ¹H-NMR (400 MHz, CDCl₃): δ 4.15 (2H, s), 364.1 (M⁺ − 1) IR (KBr,CM⁻¹): 3.27 (2H, t), 3.14 (3H, s), 2.41 (2H, s), 1.62 (2H, t), 2937.1,1722.9, 1689.4 1.06 (6H, s) 62 ¹H-NMR (400 MHz, CDCl3 + CD₃OD): δ 418.1(M⁺ − 1) IR (KBr, CM⁻¹): 15.61 (1H, s), 9.87 (1H, s), 3.30 (2H, mergedwith 2951.5, 1733.3, 1672.8 solvent peak), 2.41 (2H, s), 2.22-2.25 (2H,m), 1.88-1.95 (2H, m), 1.42-1.74 (6H, m), 1.22-1.37 (2H, m), 1.06 (6H,s) 63 ¹H-NMR (400 MHz, CDCl₃): δ 4.44-4.60 (1H, m), 434.1 (M⁺ − 1) IR(KBr, CM⁻¹): 3.68-3.70 (1H, m), 3.15-3.31 (4H, m), 2953.3, 1727.7,1670.7 2.58-2.63 (1H, m), 2.51 (3H, s), 2.41 (2H, s), 1.77-2.05 (4H, m),1.60 (2H, t), 1.05 (6H, s) 64 δ 9.71 (1H, t), 7.24-7.35 (5H, m), 4.08(2H, d), 398.1 (M⁺ − 1) IR (KBr, CM⁻¹): 2.94-3.05 (3H, m), 2.78-2.81(2H, m), 1.97-2.07 (2H, m), 2925.5, 1738.2, 1675.1 65 δ 16.22 (1H, s),9.67 (1H, t), 4.65 (2H, s), 4.08 (2H, d), 324.1 (M⁺ − 1) IR (KBr, CM⁻¹):3.91 (2H, t), 3.25 (2H, m) 3294.2, 1731.9, 1669.6 66 δ 16.20 (1H, s),9.72 (1H, t), 4.07 (2H, d), 364.1 (M⁺ − 1) IR (KBr, CM⁻¹): 3.20-3.24(1H, m), 2.77-2.82 (2H, m), 1.68-1.70 (1H, m), 3272.8, 1743.6, 1682.41.22-1.27 (4H, m), 1.08 (3H, s), 0.93 (3H, s) 67 δ 9.64 (1H, t), 4.60(2H, s), 4.09 (2H, d), 3.79 (2H, t), 372.0 (M⁺ − 1) IR (KBr, CM⁻¹):2.30-2.32 (2H, m) 3277.2, 1741.5, 1672.5 68 δ 12.67 (1H, bs), 9.47 (1H,t), 3.97 (2H, d), 372.0 (M⁺ − 1) IR (KBr, CM⁻¹): 3.84 (2H, s), 3.49 (2H,t), 2.96 (2H, t), 2.34 (3H, s) 3260.4, 1731.0, 1659.6 69 ¹H-NMR (400MHz, CDCl₃): δ 9.85 (1H, t), 426.0 (M⁺ + 1) IR (KBr, CM⁻¹): 5.40 (1H,s), 4.13-4.30 (4H, m), 3.83-3.87 (1H, m), 3247.9, 1748.2, 1667.63.65-3.69 (1H, m), 2.72-2.74 (1H, m) 2.62-2.66 (1H, m), 2.42 (3H, s),2.24-2.28 (1H, m), 2.07-2.09 (1H, m), 1.87-1.89 (1H, m), 1.63-1.68 (1H,m), 1.29 (3H, t), 1.21 (3H, t) 70 δ 16.18 (1H, s), 9.71 (1H, t), 4.08(2H, d), 3.25 (2H, t), 348.1 (M⁺ − 1) IR (KBr, CM⁻¹): 2.54 (2H, s), 1.60(2H, t), 0.45-0.47 (4H, m) 3266.4, 1716.9, 1678.2 71 δ9.50 (1H, t), 3.97(2H, d), 3.62 (2H, s), 395.0 (M⁺ − 1) IR (KBr, CM⁻¹): 3.24-3.34 (2H,partailly overlapped by water signal) 3289.6, 1668.4, 1628.05 2.88-2.95(1H, m), 2.78 (2H, t), 2.33 (3H, s), 1.05 (6H, d) 72 δ 16.20 (1H, s),9.69 (1H, t), 4.08 (2H, d), 3.34 (1H, 366.1 (M⁺ − 1) IR (KBr, CM⁻¹):merged with water signal), 3.10-3.20 (1H, m), 2976.8, 1733.1, 1684.82.85-2.95 (1H, m), 2.75-2.81 (2H, m), 2.11-2.15 (1H, m), 1.78-1.82 (1H,m) 73 δ 9.50 (1H, t), 5.82 (1H, s), 4.54-4.56 (1H, m), 446.0 (M⁺ − 1) IR(KBr, CM⁻¹): 3.98 (2H, d), 3.35-3.60 (2H, partailly overlapped by water3261.1, 1743.2, 1663.7 signal), 3.01-3.17 (2H, m), 2.35 (3H, s), 2.26(3H, s), 2.09-2.20 (5H, m) 74 δ 16.01 (1H, s), 9.88 (1H, d), 4.49 (1H,dd), 379.9 (M⁺ + 1) IR (KBr, CM⁻¹): 3.17-3.19 (2H, m), 2.63-2.65 (2H,m), 1.90-2.00 (1H, m), 3251.2, 1723.3, 1678.6 1.76-1.78 (4H, m),1.45-1.50 (1H, m), 1.20-1.25 (1H, m), 0.90-0.92 (6H, m) 75 δ 10.89 (1H,s), 9.65 (1H, d), 7.51 (1H, d), 7.32 (1H, d), 482.8 (M⁺ + 1) IR (KBr,CM⁻¹): 7.12 (1H, d), 7.05 (1H, t), 6.94 (1H, t), 4.70 (1H, q), 3279.2,1669.8, 1621.7 3.15-3.27 (4H, m), 2.63-2.67 (2H, m), 2.33 (3H, s),1.75-1.79 (4H, m) 76 δ 9.63 (1H, d), 7.59 (1H, s), 6.84 (1H, s), 4.61(1H, q), 433.8 (M⁺ + 1) IR (KBr, CM⁻¹): 3.16-3.22 (2H, m), 2.89-3.08(2H, m), 3235.1, 1717.1, 1659.3 2.65-2.69 (2H, m), 2.32 (3H, s),1.76-1.80 (4H, m) 77 δ 9.56 (1H, d), 9.24 (1H, s), 6.96 (2H, d), 458.0(M⁺ − 1) IR (KBr, CM⁻¹): 6.64 (2H, d), 4.55-4.60 (1H, m), 3.17-3.21 (2H,m), 3153.8, 1717.4, 1656.1 2.87-3.02 (2H, m), 2.65-2.69 (2H, m), 2.32(3H, s), 1.76-1.80 (4H, m) 78 δ 9.68 (1H, t), 8.54 (2H, bs), 7.38 (2H,d), 4.08 (2H, d), 413.9 (M⁺ − 1) IR (KBr, CM⁻¹): 3.76 (2H, s), 3.57 (2H,s) 3.20-3.32 (2H, partailly 3282.9, 1678.2, 1553.9 overlapped by watersignal), 2.82 (2H, t) 80 δ 9.96 (1H, t), 3.42 (2H, d), 3.09 (2H, t),2.26 (2H, s), 350.2 (M⁺ − 1) IR (KBr, CM⁻¹): 1.48 (2H, t), 0.98 (6H, s)3284.1, 1658.2, 1612.6 82 ¹H-NMR (400 MHz, D₂O): δ 3.80 (2H, s), 336.1(M⁺ − 1) IR (KBr, CM⁻¹): 3.30-3.32 (2H, m), 2.54-2.57 (2H, m), 1.60-1.72(6H, m) 3247.6, 1609.3, 1540.9 83 δ 9.76 (2H, t), 8.99 (1H, bs), 7.85(4H, bs), 336.2 (M⁺ − 1) IR (KBr, CM⁻¹): 3.88 (4H, d), 3.56-3.59 (5H,m), 3.31 (2H, t), 3279.4, 1677.0, 1564.2 3.08-3.10 (2H, m), 2.75-2.77(4H, m), 1.80-1.81 (4H, m), 1.62-1.64 (8H, m), 1.57-1.60 (2H, m) 84¹H-NMR (400 MHz, D₂O): δ 3.75 (2H, bs), 336.2 (M⁺ − 1) IR (KBr, CM⁻¹):3.63 (1H, t), 3.27-3.29 (2H, m), 2.90 (2H, t),, 2917.2, 1655.4, 1559.12.58-2.60 (2H, m), 1.57-1.81 (10H, m), 1.28-1.42 (2H, m) 85 ¹H-NMR (400MHz, D₂O): δ 3.79 (2H, bs), 336.1 (M⁺ − 1) IR (KBr, CM⁻¹): 3.26-3.29(2H, m), 2.50-2.52 (2H, m), 1.67-1.68 (2H, m), 2921.7, 1656.6, 1562.51.57-1.60 (4H, m) 86 δ 9.79 (1H, bs), 3.88 (2H, d), 3.55-3.57 (2H, m),336.2 (M⁺ − 1) IR (KBr, CM⁻¹): 2.66-2.68 (2H, m), 1.79-1.80 (2H, m),2931.4, 1662.4, 1550.2 1.69-1.71 (4H, m), 87 δ 4.03-4.07 (2H, m),3.55-3.66 (2H, m), 336.2 (M⁺ − 1) IR (KBr, CM⁻¹): 2.66-2.76 (2H, m),1.78-1.87 (6H, m), 2933.6, 1678.9, 1558.7 88 ¹H-NMR (400 MHz, D₂O): δ3.78 (2H, s), 338.0 (M⁺ + 1) IR (KBr, CM⁻¹): 3.28-3.30 (2H, m),2.54-2.57 (2H, m), 1.60-1.70 (6H, m) 2743.3, 1663.9, 1590.0 89 ¹H-NMR(400 MHz, D₂O): δ 3.80 (2H, s), 336.2 (M⁺ − 1) IR (KBr, CM⁻¹): 3.34-3.36(2H, m), 2.96 (4H, q), 2.61-2.64 (2H, m), 2933.4, 1673.3, 1650.61.67-1.77 (6H, m), 1.15 (6H, t) 90 δ 9.78 (1H, s), 3.85-3.86 (2H, m),3.66-3.68 (2H, m), 336.2 (M⁺ − 1) IR (KBr, CM⁻¹): 3.50 (2H, d), 3.42(2H, t), 3.12 (9H, s), 2.70-2.72 (2H, 2927.5, 1675.9, 1608.4 m),1.79-1.80 (2H, m), 1.69-1.70 (4H, m), 91 δ 9.77 (1H, t), 3.70 (2H, d),3.56-3.59 (2H, m), 338.2 (M⁺ + 1) IR (KBr, CM⁻¹): 3.46 (6H, merged withwater peak), 2.74-2.76 (2H, m), 2925.9, 1652.6, 1558.9 1.80-1.81 (2H,m), 1.69-1.71 (4H, m), 92 ¹H-NMR (400 MHz, D₂O): δ 8.05 (1H, d), 338.0(M⁺ + 1) IR (KBr, CM⁻¹): 7.08 (1H, d), 3.88 (1H, dd), 3.76 (2H, s),3.28-3.30 (2H, m), 2949.4, 1740.7, 1679.2 3.06-3.23 (2H, m), 2.60-2.61(2H, m), 1.66-1.71 (6H, m) 93 δ 9.45 (1H, t), 7.46 (1H, s), 7.12 (1H,s), 3.84 (2H, d), 367.1 (M⁺ + 1) IR (KBr, CM⁻¹): 3.59-3.61 (2H, m),2.79-2.81 (2H, m), 2.33 (3H, s), 3355.1, 1701.7, 1654.6 1.81-1.82 (2H,m), 1.70-1.71 (4H, m) 94 δ 10.62 (1H, bs), 9.47 (1H, T), 8.89 (1H, s),383.0 (M⁺ + 1) IR (KBr, CM⁻¹): 3.80 (2H, d), 3.59-3.61 (2H, m),2.79-2.81 (2H, m), 3264.1, 1661.3, 1605.7 2.33 (3H, s), 1.68-1.82 (6H,m), 95 ¹H-NMR (400 MHz, CDCl₃): δ 490.3 (M⁺ − 1) IR (KBr, CM⁻¹):7.22-7.39 (4H, m), 5.45-5.49 (0.4H, m), 4.63-4.67 (0.6H, m), 2928.0,1742.7, 1662.2 4.39-4.50 (1H, m), 4.05-4.07 (1H, m), 3.63-3.91 (3H, m),2.75 (2H, bs), 2.55 (3H, d), 1.68-1.83 (6H, m), 96 ¹H-NMR (400 MHz,CDCl₃): δ 4.00-4.02 (1H, m), 462.3 (M⁺ − 1) IR (KBr, CM⁻¹): 3.74-3.78(1H, m), 3.54-3.59 (2H, m), 2944.7, 1717.1, 1674.7 3.40-3.44 (1H, m),2.71 (2H, t), 2.50-2.56 (4H, m), 2.05-2.07 (2H, m), 1.24-1.91 (15H, m),97 ¹H-NMR (400 MHz, CDCl₃): δ 16.01 (1H, s), 391.1 (M⁺ + 1) IR (KBr,CM⁻¹): 10.23 (1H, t), 4.16 (2H, d), 3.65-3.67 (2H, m), 3.54 (2H, t),2931.1, 1677.2, 1566.0 3.44 (2H, t), 2.67-2.69 (2H, m), 2.00-2.03 (2H,m), 1.87-1.91 (4H, m), 1.74-1.76 (4H, m) 99 ¹H-NMR (400 MHz, CDCl₃): δ15.63 (1H, s), 425.3 (M⁺ − 1) IR (KBr, CM⁻¹): 9.95 (1H, t), 7.26-7.35(5H, m), 6.35 (1H, bs), 4.49 (2H, d), 2932.3, 1685.6, 1533.9 4.14 (2H,d), 3.61-3.64 (2H, m), 2.69-2.72 (2H, m), 1.60-1.89 (6H, m), 100 ¹H-NMR(400 MHz, CDCl₃): δ 4.17-4.21 (2H, m), 432.2 (M⁺ − 1) IR (KBr, CM⁻¹):3.62-3.64 (2H, m), 3.41-3.49 (3H, m), 2926.3, 1730.5, 1678.2 2.69-2.71(2H, m), 2.43 (2H, t), 1.41-2.04 (12H, m), 1.19-1.29 (2H, m) 101 δ12.02-12.52 (1H, m), 7.26-7.35 (5H, m), 4.71 (1H, s), 426.2 (M⁺ − 1) IR(KBr, CM⁻¹): 4.52 (1H, s), 3.66 (2H, d), 3.57-3.59 (2H, m), 2928.6,1737.8, 1676.6 2.67-2.73 (2H, m), 1.78-1.80 (2H, m), 1.66-1.68 (4H, m)

Combination Therapy

Compounds of the present invention may be administered in combinationwith other drugs that are used in the treatment/prevention/suppressionor amelioration of the diseases or conditions for which compounds ofFormula (I) are useful. Such other drugs may be administeredcontemporaneously or sequentially with a compound of Formula (I). When acompound of Formula (I) is used contemporaneously with one or more otherdrugs, a pharmaceutical composition containing such other drugs inaddition to the compound of Formula (I) is preferred. Accordingly, thepharmaceutical compositions of the present invention include those thatalso contain one or more other active ingredients, in addition to acompound of Formula (I).

Pharmaceutical Compositions

In another embodiment of the invention, there is provided apharmaceutical composition comprising a therapeutically effective amountof one or more of a compound of formula (I). While it is possible toadminister therapeutically effective quantity of compounds of formula(I) either individually or in combination, directly without anyformulation, it is common practice to administer the compounds in theform of pharmaceutical dosage forms comprising pharmaceuticallyacceptable excipient(s) and at least one active ingredient. These dosageforms may be administered by a variety of routes including oral,topical, transdermal, subcutaneous, intramuscular, intravenous,intraperitoneal, intranasal, pulmonary etc.

Oral compositions may be in the form of solid or liquid dosage form.Solid dosage form may comprise pellets, pouches, sachets or discreteunits such as tablets, multi-particulate units, capsules (soft & hardgelatin) etc. Liquid dosage forms may be in the form of elixirs,suspensions, emulsions, solutions, syrups etc. Composition intended fororal use may be prepared according to any method known in the art forthe manufacture of the composition and such pharmaceutical compositionsmay contain in addition to active ingredients, excipients such asdiluents, disintegrating agents, binders, solubilizers, lubricants,glidants, surfactants, suspending agents, emulsifiers, chelating agents,stabilizers, flavours, sweeteners, colours etc. Some example of suitableexcipients include lactose, cellulose and its derivatives such asmicrocrystalline cellulose, methylcellulose, hydroxy propyl methylcellulose & ethylcellulose, dicalcium phosphate, mannitol, starch,gelatin, polyvinyl pyrolidone, various gums like acacia, tragacanth,xanthan, alginates & its derivatives, sorbitol, dextrose, xylitol,magnesium Stearate, talc, colloidal silicon dioxide, mineral oil,glyceryl mono stearate, glyceryl behenate, sodium starch glycolate,cross povidone, crosslinked carboxymethylcellulose, various emulsifierssuch as polyethylene glycol, sorbitol, fatty acid esters, polyethyleneglycol alkylethers, sugar esters, polyoxyethylene polyoxypropyl blockcopolymers, polyethoxylated fatty acid monoesters, diesters and mixturesthereof.

Sterile compositions for injection can be formulated according toconventional pharmaceutical practice by dissolving or suspending theactive substance in a vehicle such as water for injection,N-Methyl-2-Pyrrolidone, propylene glycol and other glycols, alcohols, anaturally occurring vegetable oil like sesame oil, coconut oil, peanutoil, cotton seed oil or a synthetic fatty vehicle like ethyl oleate orthe like. Buffers, anti-oxidants, preservatives, complexing agents likecellulose derivatives, peptides, polypeptides and cyclodextrins and thelike can be incorporated as required.

The dosage form can have a slow, delayed or controlled release of activeingredients in addition to immediate release dosage forms.

The amount of active ingredient which is required to achieve atherapeutic effect will, of course, vary with the particular compound,the route of administration, the subject under treatment, and theparticular disorder or disease being treated. The compounds of theinvention may be administered orally or parentally at a dose of from0.001 to 1500 mg/kg per day, preferably from 0.01 to 1500 mg/kg per day,more preferably from 0.1 to 1500 mg/kg per day, most preferably from 0.1to 500 mg/kg per day. The dose range for adult humans is generally from5 mg to 35 g per day and preferably 5 mg to 2 g per day.

Dosage forms of presentation provided in discrete units may convenientlycontain an amount of compound of the invention which is effective atsuch dosage or as a multiple of the same, for example units containing 5mg to 500 mg.

Examples of Pharmaceutical Composition:

Quantity No. Ingredient (%) 1 Compound no. 10 0.005 to 0.5 2 PhosphateBuffer Q.S. Saline pH 7.4

Accurately weighed quantity of compound no. 10 was dissolved inphosphate buffer saline (pH 7.4) under aseptic environment. The solutionwas filtered through 0.22 micron filter and filled into presterilizedglass vials. The solution was purged with nitrogen during process. Thesevials were further terminally sterilized by autoclave.

Biological Testing: In Vitro Erythropoietin Induction:

Hep3B cell line (ATCC HB8064) was employed. Induction of erythropoietinwas carried out for the indicated dose of compounds for 16 hoursduration. At the end of 16 hours, cell culture medium was collected andcentrifuged to remove any debris. Supernatant obtained was analyzed forerythropoietin by ELISA (R&D systems, USA). The results were expressedas fold induction as compared to vehicle control.

TABLE 2 Concentration Compound No. uM EPO fold induction 1 50 +++ 2 200+++ 3 200 ++ 4 200 ++ 5 200 ++ 6 200 + 7 200 ++ 8 200 ++ 9 200 +++ 10200 +++++ 11 200 +++ 12 50 ++ 13 200 + 14 200 ++ 15 200 + 16 200 +++ 17200 ++ 18 200 ++++ 19 200 ++ 20 200 +++ 21 200 ++++ 22 200 +++ 23 200++++ 24 200 +++ 25 200 ++ 26 200 ++++ 27 200 ++++ 28 200 ++++ 29 200++++ 30 200 + 31 200 +++ 32 200 ++++ 33 200 ++ 34 200 +++++ 35 200 + 3612.5 + 37 200 +++ 38 200 ++++ 39 200 ++ 40 200 +++ 41 200 ++ 42 200 +++43 200 + 44 200 + 46 50 ++ 49 200 +++ 53 200 + 54 200 + 55 200 + 52 200+++ 56 200 + 57 200 + 58 200 +++ 59 200 + 60 200 +++ 61 200 + 64 200 +65 200 +++ 67 200 ++ 70 200 ++ 72 200 + 80 200 ++++ 82 50 ++++ +indicates <2 fold; ++ indicates 2-4 fold; +++ indicates 5-8 fold; ++++indicates 9-16 fold; +++++ indicates >16 fold induction oferythropoietin respectively, relative to vehicle control.

Above data indicates that the compounds of the present inventionsignificantly elevate the expression of erythropoietin in cells.

In Vitro Induction of Adrenomedullin:

Hep3B cell line (ATCC HB8064) was employed. Induction of adrenomedullinwas carried out for the indicated dose of compounds for 6 hoursduration. At the end of 6 hours, cells were lysed and total RNA wasisolated. Expression of adrenomedullin mRNA along-with expression of 18SrRNA was monitored by real-time PCR. Adrenomedullin mRNA expression wasnormalized relative to the expression of 18S rRNA. The results wereexpressed as fold induction of adrenomedullin mRNA relative to vehicletreated control.

TABLE 3 Concentration Adrenomedullin mRNA Compound No. (uM) (foldinduction) 10 200 ++++ 23 200 ++ 27 200 ++++ 32 200 ++ 34 200 +++ 49 200+++ 52 200 +++ 82 200 +++ + indicates <2 fold; ++ indicates 2-4 fold;+++ indicates 5-8 fold; ++++ indicates >8 fold induction ofadrenomedullin mRNA respectively, relative to vehicle control.

Above data indicates that the compounds of the present inventionsignificantly elevate the expression of adrenomedullin in cells.

In Vitro Induction of Vascular Endothelial Growth Factor (VEGF):

Hep3B cell line (ATCC HB8064) was employed. Induction of VEGF wascarried out for the indicated dose of compounds for 16 hours duration.At the end of 16 hours, cell culture medium was collected andcentrifuged to remove any debris. Supernatant obtained was analyzed forVEGF by ELISA (R&D systems, USA). The results were expressed as foldinduction as compared to vehicle control.

TABLE 4 Compound VEGF No. Concentration (uM) (Fold induction) 10 200 ++23 200 ++ 27 200 ++ 32 200 ++ 34 200 ++ 82 200 ++ + indicates <2 fold;++ indicates 2-4 fold induction of VEGF relative to vehicle control

Above data indicates that the compounds of the present inventionsignificantly elevate the expression of VEGF in cells.

Effect of Compounds of Present Invention on Anemia Associated withChronic Kidney Disease (CKD):

The efficacy of the test compound to correct anemia associated with CKDwas studied in an animal model of anemia—⅚ nephrectomized (⅚ NX)rats^(15,16,17). Animals were randomized based upon anemia and kidneydysfunction parameters and divided into two groups. One group receivedcompound—10 (20 mg/kg; b.i.d. i.p) for seven days while the controlreceived respective vehicle. Blood sampling was done on day 3 and 7 postinitiation of drug administration to check early markers of anemiacorrection.

Results:

Treatment with the test compound resulted in significant increase incirculating EPO levels ranging from 115-3900 pg/ml as compared withundetectable levels (<45 pg/ml) of circulating EPO in vehicle control.There was 3 and 5.6 fold increase in reticulocyte production index onday 3 and day 7 respectively compared to control group with testcompound treatment. Similarly, there was 30%, 25% and 24% increase inhemoglobin content, hematocrit percent and erythrocyte countrespectively on day 7 of treatment compared to control.

Effect of Compound of Present Invention on Ischemia-Reperfusion Injuryto Kidney:

The efficacy of test compound to improve renal function was evaluated ina renal ischemia and reperfusion induced acute kidney injury model inrats. The beneficial effect of the compound was evaluated using twodifferent treatment protocols. In one protocol treatment with testcompound was given before onset of ischemia (pre-treatment) and theother protocol involved treatment with test compound initiated after theonset of ischemia (post-treatment).

Pre-ischemia intervention protocol: Rats were randomised into twogroups, compound treated and vehicle control. Before initiation ofbilateral renal ischemia, the animals in compound treatment groupreceived multiple doses of compound no. 10 (i.e. pre treated) andcontrol group received vehicle by i.p route.

Post-ischemia intervention protocol: Rats were randomised into twogroups, compound treated and vehicle control. After initiation ofbilateral renal ischemia, the animals in compound treatment groupreceived multiple doses of compound no. 10 (i.e. post treated) andcontrol group received vehicle in similar fashion by i.p route.

Induction of Renal ischemia and reperfusion in rats: All animals wereanesthetized with pentobarbital sodium (50 mg/kg body wt). Homeothermicblanket was used to maintain a constant body temperature of 37° C.during surgery and ischemia. A midline incision was made at the ventralside to access the kidneys and both renal pedicle were isolated andoccluded for 35 mins using microclips, which was verified by the changeof the renal color. After an ischemic period of 35 min, the microclipswere removed and reperfusion initiated. The abdomen was closed and skin& muscles sutured and animal allowed to recover. Blood sample of 300 μlwas taken via sublingual vein puncture at various predetermined timepoints.

Results:

In both protocols tested i.e pre-ischemia intervention and post-ischemiaintervention, renal function improvement was assessed by measuring serumcreatinine and BUN (blood urea nitrogen) at various time points postischemia. Results are expressed below as % reduction from their controlgroup at 24 hrs post initiation of ischemia.

Pre-Ischemia Intervention:

TABLE 5 i.p. Dose % reduction Compound No. (mg/kg) Ser. Creatinine BUNCompound-10 10 33.0 18.0 (Multiple dose)

Post-Ischemia Intervention:

TABLE 6 i.p. Dose % reduction Compound No. (mg/kg) Ser. Creatinine BUNCompound-10 0.3 mg/kg as 1st dose & 31.0 17.0 (Multiple dose) 0.1 mg/kgas subsequent dose

REFERENCES

-   1. Schofield C J & Ratcliffe P J (2004) Nature Review Molecular Cell    Biology; 5; 343-354-   2. Scmenza G L (2000) J Appl Physiol; 88; 1474-1480-   3. Weidemann A et al. (2008) J Am Soc Nephrol; 19; 486-494-   4. Bernhardt W M et al. (2006) J Am Soc Nephrol; 17; 1970-1978-   5. Hill P et al (2008) J Am Soc Nephrol; 19; 39-46-   6. Siddiq A et al. (2005) J Biol Chem; 280; 50; 41732-43-   7. Nangaku M (2007) J Am Soc Nephrol; 18; 13-15-   8. Amador A et al. (2007) Am J Transplantation; 7; 2180-2189-   9. Fisher J W (2003) Exp Biol Med; 228; 1-14-   10. Binley K et al. (2002) Blood; 100; 2406-2413-   11. Luo Y H et al. (2009) Hepatobiliary Pancreat Dis Int; 8; 294-299-   12. Siren A L et al. (2000) PNAS; 98; 7; 4044-49-   13. Sharples E J et al. (2004) J Am Soc Nephrol; 15; 2115-2124-   14. Looi Y H et al. (2006) Br J Pharmacol; 148; 599-609-   15. Hahn S, et al (1999); Pediatr Nephrol; 13; 195-198-   16. Priyadarshi A, et al (2002) Kidney Int; 61; 542-546-   17. Shapiro J I, et al (1990) Am J Physiol; 258; 183-188

1. A Compound of formula (I)

their pharmaceutically acceptable salts and their isomers,stereoisomers, conformers, tautomers, polymorphs, hydrates, andsolvates; Wherein, When Y is NR₄, O, S or SO₂, m is 1 to 2 and when Y isC(R₅)(R₆), m is 1 to 4; n is 1 to 6; P is —OH, —OR₇, —NH₂, —NHR₇,—NR₇R_(7′), —NHSO₂R₇, —NHCOR₇, —NHOH or —NHOR₇; X is —OH, —OR₇, —SR₇,—SOR₇, —SO₂R₇, —NHR₇ or —NR₇R_(7′); Z is S or O; R is hydrogen, linearor branched (C₁-C₈)alkyl, —(C₁-C₈)alkylaryl or —(C₁-C₈)alkylheteroaryl;R₁ and R₂ are independently selected from hydrogen, linear or branched—(C₁-C₈)alkyl, —(C₃-C₇) cycloalkyl, aryl, heteroaryl, —CH₂-aryl and—CH₂-heteroaryl, or R₁ and R₂ may join together to form a 3-6 memberedmonocyclic or 9-12 membered bicyclic ring; R together with either R₁ orR₂ of adjacent carbon atom may form a 3-6 membered monocyclic or 8-11membered bicyclic heteroaryl or heterocyclyl ring; R₃ and R_(3′) at eachoccurrence is independently selected from hydrogen, linear or branched(C₁-C₈)alkyl, (C₁-C₅) alkoxy and halo; R₃ and R_(3′) may also present ingem di-halo, gem di-alkyl or spirocycloalkyl arrangement; R₄ is selectedfrom the group consisting of hydrogen, linear or branched (C₁-C₈) alkyl,(C₃-C₇) cycloalkyl, aryl, heteroaryl, —(C₁-C₈) alkyl-aryl,—(C₁-C₈)alkyl-heteroaryl, —(C₁-C₂)alkyl-heterocyclyl, —C(O)R₈, —C(O)OR₈,—C(O)NR₈R₉, —C(S)NR₈R₉ and —SO₂R₈, wherein aryl and heteroaryl radicalsare optionally substituted with one or more substituent selected fromthe group consisting of —(C₁-C₈) alkyl, —(C₃-C₇) cycloalkyl,heterocyclyl, aryl, heteroaryl, —OH, -alkoxy, halo, CN, —CF₃, —OCF₃,—O-aryl, —SO₂—(C₁-C₈)-alkyl, —SO₂-aryl, —NH₂, —NHR₁₀, —NR₁₀R_(10′),—NH—CO—(C₁-C₈) alkyl, —NH—SO₂—(C₁-C₈)alkyl, —NH—SO₂-aryl, —COOH,—C(O)NH-alkyl, —CONH-aryl, —CONH-heteroaryl, —C(O)O—(C₁-C₈)alkyl,—C(O)O-aryl, —SO₂NH—(C₁-C₈)alkyl, —SO₂NH-aryl and —SO₂NH-heteroaryl; R₅and R₆ are independently selected from the group consisting of hydrogen,linear or branched (C₁-C₈)alkyl, (C₃-C₇) cycloalkyl, aryl, heteroaryl,fluoro, —COOH, —CONH—(C₁-C₈)alkyl, —NHCO—(C₁-C₈)alkyl, —NHCO-aryl,—NHCO-heteroaryl, —NH—SO₂(C₁-C₈)alkyl, —NH—SO₂-aryl and—NH—SO₂-heteroaryl; R₅ and R₆ may join together to form a 3-6 memberedcarbocyclic, heteroaryl or heterocyclyl ring; R₇, R_(7′), R₁₀ andR_(10′) are independently selected from linear or branched (C₁-C₈)alkyl,(C₃-C₇) cycloalkyl and —(C₁-C₈)alkylaryl; R₇ and R_(7′) or R₁₀ andR_(10′) together with nitrogen atom to which they are attached, may form5-6 membered monocyclic or 8-14 membered bicyclic saturated andpartially saturated ring. The ring may contain 1 to 3 heteroatomselected from N, S & O. Wherein saturated and partially saturated ringmay be optionally substituted with one or more substituent independentlyselected from the group consisting of —(C₁-C₈)alkyl, —(C₃-C₇)cycloalkyl, heterocyclyl, aryl, heteroaryl, —OH, -alkoxy, halo, —CN,—CF₃, —OCF₃, —O-aryl, —SO₂—(C₁-C₈)-alkyl, —SO₂-aryl, —NH₂, —NHR₁₀,—NR₁₀R_(10′), —NH—CO—(C₁-C₈)alkyl, —NH—SO₂—(C₁-C₈)alkyl, —NH—SO₂-aryl,—COOH, —C(O)NH-alkyl, —CONH-aryl, —CONH-heteroaryl, —C(O)O—(C₁-C₈)alkyl,—C(O)O-aryl, —SO₂NH—(C₁-C₈)alkyl, —SO₂NH-aryl and —SO₂NH-heteroaryl; R₈is selected from the group consisting of linear or branched (C₁-C₈)alkyl, (C₃-C₇) cycloalkyl, —(C₁-C₈)alkyl-(C₃-C₇)cycloalkyl,heterocyclyl, aryl, —(C₁-C₈)alkyl-aryl, —(C₁-C₂)alkyl-heterocyclyl,heteroaryl and —(C₁-C₈)alkyl-heteroaryl, wherein aryl and heteroarylradicals are optionally substituted with one or more substituentselected from linear or branched (C₁-C₈)alkyl, (C₃-C₇)cycloalkyl,—(C₁-C₈)alkyl-(C₃-C₇)cycloalkyl, aryl, heteroaryl, heterocyclyl, —OH,alkoxy, halo, —CN, —CF₃, —OCF₃, —O-aryl, —SO₂—(C₁-C₈)alkyl, —SO₂-aryl,—NH₂, —NHR₁₀, —NR₁₀R_(10′), —NH—CO—(C₁-C₈)alkyl, —NH—SO₂—(C₁-C₈)alkyl,—C(O)OH, —C(O)NH—(C₁-C₈)alkyl, —CONH-aryl, —CONH-heteroaryl,—NHCONH—(C₁-C₈)alkyl, —NHCONH-aryl, —SO₂NH—(C₁-C₈)alkyl, —SO₂NH-aryl and—SO₂NH-heteroaryl; R₉ is hydrogen, linear or branched (C₁-C₈)alkyl or—(C₁-C₈)alkylaryl; R₈ and R₉ together with nitrogen atom to which theyare attached, may form 5-6 membered saturated ring.
 2. The compound asclaimed in claim 1, which is selected from the group consisting of:[(2-Hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid;3-(Carboxymethyl-carbamoyl)-2-hydroxy-4-oxo-5,8-dihydro-4H,6H-9-thia-1,4a,7-triaza-fluorene-7-carboxylicacid ethyl ester;[(2-Hydroxy-7-methanesulfonyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-aceticacid;{[2-Hydroxy-7-(3-methyl-butyryl)-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[2-Hydroxy-4-oxo-7-(propane-2-sulfonyl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;1-[(2-Hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-cyclopentanecarboxylicacid;{[2-Hydroxy-4-oxo-7-(toluene-4-sulfonyl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;[(2-Hydroxy-4-oxo-7-phenylcarbamoyl-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-aceticacid;[(7-Cyclopropanecarbonyl-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-aceticacid;[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid;[(2-Hydroxy-4-oxo-7,8-dihydro-4H,6H-cyclopenta[4,5]thiazolo[3,2-a]pyrimidine-3-carbonyl)-amino]-aceticacid;[(2-Hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid, sodium salt;[(7-tert-Butyl-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid;3-[(2-Hydroxy-4-oxo-7,8-dihydro-4H,6H-cyclopenta[4,5]thiazolo[3,2-a]pyrimidine-3-carbonyl)-amino]-propionicacid;3-[(7-tert-Butyl-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-propionicacid;{[7-(4-Fluoro-benzoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[7-(5-Chloro-thiophene-2-sulfonyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[2-Hydroxy-4-oxo-7-(5-trifluoromethyl-pyridin-2-yl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[2-Hydroxy-4-oxo-7-(4-trifluoromethoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[7-(2,2-Dimethyl-propionyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[7-(4-Butyl-benzoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[2-Hydroxy-4-oxo-7-(4-trifluoromethoxy-benzoyl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[7-(4-Chloro-benzyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[7-(4-Fluoro-phenylthiocarbamoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;[(2-Hydroxy-7-isopropylthiocarbamoyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-aceticacid;3-(Carboxymethyl-carbamoyl)-2-hydroxy-4-oxo-5,8-dihydro-4H,6H-9-thia-1,4a,7-triaza-fluorene-7-carboxylicacid benzyl ester;{[7-(2-Cyclopropyl-acetyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;({7-[2-(4-Chloro-phenyl)-acetyl]-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl}-amino)-aceticacid;{[7-(2-Cyclopentyl-acetyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;3-[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-propionicacid;{[2-Hydroxy-7-(4-methoxy-benzyl)-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;2-[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-propionicacid;{[7-(6-Chloro-pyridine-3-carbonyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid;{[7-(6-Chloro-pyridazin-3-yl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[7-(3-Cyano-pyridin-2-yl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[7-(3-Chloro-4-methoxy-benzoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;[(2-Hydroxy-4-oxo-5,6,7,8,9,10-hexahydro-4H-11-thia-1,4a-diaza-cycloocta[a]indene-3-carbonyl)-amino]-aceticacid;[(2-Hydroxy-7-indan-5-ylmethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-aceticacid;2-[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-propionicacid;{[7-(3,5-Dimethoxy-benzoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[2-Hydroxy-7-(4-methanesulfonyl-benzoyl)-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;2-[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-3-methyl-butyricacid (L-isomer);2-[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-propionicacid (D-isomer);{[7-(3,5-Dichloro-4-methoxy-benzoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[7-(3,5-Bis-trifluoromethyl-benzyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[2-Hydroxy-4-oxo-7-(4-propyl-benzoyl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[7-(3,5-Bis-trifluoromethyl-benzoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[7-(3,4-Dichloro-benzyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;[(2-Hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-aceticacid, hydrochloride salt;{[2-Hydroxy-7-(7-methoxy-6-methyl-indan-4-ylmethyl)-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;{[2-Hydroxy-4-oxo-7-(4-trifluoromethyl-benzyl)-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl]-amino}-aceticacid;[(7,7-Diethyl-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid;2-[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-2-methyl-propionicacid;[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-phenyl-aceticacid, L-isomer;[(7-Benzoylamino-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid;[(2-Hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-oxa-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid;[(2-Hydroxy-7-methyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid;[(2-Hydroxy-4-oxo-7-propyl-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid;[(2-Hydroxy-6,6-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid;[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-methyl-amino]-aceticacid;1-[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-cyclohexanecarboxylicacid;1-(7,7-Dimethyl-2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-piperidine-4-carboxylicacid;[(2-Hydroxy-4-oxo-7-phenyl-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid;[(2-Hydroxy-4-oxo-5,8-dihydro-4H,6H-7-oxa-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid;[(2-Hydroxy-5,7,7-trimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid;[(2-Hydroxy-4,7,7-trioxo-5,6,7,8-tetrahydro-4H-7lambda*6*,9-dithia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid;[(2-Methylsulfanyl-4-oxo-5,8-dihydro-4H,6H-7,9-dithia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid;[(5-Ethoxy-2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid ethyl ester;N-[(2′-hydroxy-4′-oxo-6′,9′-dihydro-4′H,7′H-spiro[cyclopropane-1,8′-pyrimido[2,1-b][1,3]benzothiazol]-3′-yl)carbonyl]glycine;[(7-Isopropyl-2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-aceticacid;3-(Carboxymethyl-carbamoyl)-2-hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-7-carboxylicacid;{[7-(3,5-Dimethyl-pyrazol-1-yl)-2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl]-amino}-aceticacid;2-[(2-Hydroxy-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-3-methyl-pentanoicacid (L-isomer);3-(1H-Indol-2-yl)-2-[(2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-propionicacid (L-isomer);3-(3H-Imidazol-4-yl)-2-[(2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-propionicacid (L-isomer);3-(4-Hydroxy-phenyl)-2-[(2-methylsulfanyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-propionicacid (L-isomer);[(2-Hydroxy-4-oxo-7-pyridin-4-ylmethyl-5,6,7,8-tetrahydro-4H-9-thia-1,4a,7-triaza-fluorene-3-carbonyl)-amino]-aceticacid;2-Methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylicacid (2-oxo-2-pyrrolidin-1-yl-ethyl)-amide;[(2-Hydroxy-7,7-dimethyl-4-oxo-5,6,7,8-tetrahydro-4H-9-thia-1,4a-diaza-fluorene-3-carbonyl)-amino]-aceticacid, Disodium salt;[(2-Ethoxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid;[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid, Disodium salt;[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid, arginine salt (2:1);[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid, lysine salt;[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid, dipotassium salt;[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid, calcium salt (2:1);[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid, magnesium salt (2:1);[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid, ammonium salt;[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid, diethylamine salt;[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid, choline salt;[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid, tromethamine salt;[(2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid, histidine salt;2-Methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylicacid carbamoylmethyl-amide;2-Methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylicacid hydroxycarbamoylmethyl-amide;[(4-Chloro-benzyl)-(2-methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid;4-[Cyclopentyl-(2-methylsulfanyl-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-butyricacid;2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylicacid (2-oxo-2-pyrrolidin-1-yl-ethyl)-amide;2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylicacid cyclohexylcarbamoylmethyl-amide;2-Hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carboxylicacid (benzylcarbamoyl-methyl)-amide;4-[Cyclopentyl-(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-butyricacid;[Benzyl-(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-aceticacid and pharmaceutically acceptable salts thereof.
 3. A pharmaceuticalcomposition comprising a therapeutically effective amount of one or morecompound of claim 1, in association with a pharmaceutically acceptableadjuvant, diluent or carrier.
 4. A method of treating anemia in amammal, including human being, the method comprising administering atherapeutically effective amount of a compound of claim
 1. 5. A methodof treating anemia of elderly or anemia associated with conditions likechronic diseases, renal failure, cancer, infection, dialysis, surgery,and chemotherapy in a mammal, the method comprising administering atherapeutically effective amount of a compound of claim
 1. 6. A methodfor prevention or treatment of tissue damage caused by renal ischemia,cardiovascular ischemia, cerebrovascular ischemia, hepatic ischemia orperipheral vascular ischemia in a mammal, including human being, themethod comprises administering a therapeutically effective amount of acompound of claim
 1. 7. A method of prevention or treatment of tissuedamage caused by ischemic disorders including acute kidney injury,myocardial infarction, stroke, hepatic ischemia-reperfusion injury andperipheral vascular diseases in a mammal, including human being, themethod comprises administering a therapeutically effective amount of acompound of claim 1.